Immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL)

ABSTRACT

The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to several novel peptide sequences and their variants derived from HLA class I and HLA class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/965,212, filed Apr. 27, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/743,335, filed Jun. 18, 2015 (now U.S. Pat. No.10,000,533), which claims priority to U.S. Provisional Application62/014,849, filed Jun. 20, 2014, GB 1411037.3, filed Jun. 20, 2014, andPCT/EP2015/063566, filed Jun. 17, 2015. Each of these applications isincorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED AS A COMPLIANT ASCII TEXT FILE(.TXT)

A Sequence Listing is submitted herewith as an ASCII compliant text filenamed “2912919-036003_Sequence_Listing_ST25.txt”, created on Sep. 10,2018, and having a size of 178,108 bytes as permitted under 37 C.F.R. §1.821(c). The material in the aforementioned text file is herebyincorporated by reference in its entirety.

BACKGROUND Field of the Invention

The present invention relates to peptides, nucleic acids and cells foruse in immunotherapeutic methods. In particular, the present inventionrelates to the immunotherapy of cancer. The present inventionfurthermore relates to tumor-associated cytotoxic T cell (CTL) peptideepitopes, alone or in combination with other tumor-associated peptidesthat serve as active pharmaceutical ingredients of vaccine compositionsthat stimulate anti-tumor immune responses. The present inventionrelates to several novel peptide sequences and their variants derivedfrom HLA class I and HLA class II molecules of human tumor cells thatcan be used in vaccine compositions for eliciting anti-tumor immuneresponses.

Description of Related Art

B-cell chronic lymphocytic leukemia (B-CLL), also known as chroniclymphoid leukemia (CLL), is the most common type of leukemia.

Leukemias are cancers of the white blood cells (leukocytes). CLL affectsB cell lymphocytes. B cells originate in the bone marrow, develop in thelymph nodes, and normally fight infection by producing antibodies. InCLL, B cells grow out of control and accumulate in the bone marrow andblood, where they crowd out healthy blood cells. CLL is a stage of smalllymphocytic lymphoma (SLL), a type of B-cell lymphoma, which presentsprimarily in the lymph nodes. CLL and SLL are considered the sameunderlying disease, just with different appearances.

CLL is a disease of adults, but, in rare cases, it can occur inteenagers and occasionally in children (inherited). Most (>75%) peoplenewly diagnosed with CLL are over the age of 50, and the majority aremen, with a median age of 70 years at the time of diagnosis. Though lesscommon, CLL sometimes affects people between 30 and 39 years of age. Theincidence of CLL increases very quickly with increasing age.

In the United States, during 2012 about 16,060 new cases are expected tobe diagnosed, and 4,580 patients are expected to die from CLL.

CLL is very rare in Asian countries, such as Japan and China, and mayaccount for as few as 10 percent of all leukemias in those regions.

In view of the above, there remains a need for new efficacious and safetreatment option for cancers, in particular chronic lymphoid leukemia(CLL) and other cancers of the blood of different phenotypes whichimprove the well-being of the patients by not using excessivechemotherapeutic agents or other agents that may lead to severe sideeffects.

SUMMARY

The present invention employs peptides that stimulate the immune systemof the patient and act as anti-tumor-agents in a non-invasive fashion.

In a first aspect of the present invention, the present inventionrelates to a peptide comprising an amino acid sequence selected from thegroup of SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO:542 or SEQ ID NO: 543 to SEQ ID NO: 1016 or a variant sequence thereofwhich is at least 80%, preferably at least 90%, homologous (preferablyat least 80% or at least 90% identical) to SEQ ID NO: 1 to SEQ ID NO:225 or SEQ ID NO: 543 to SEQ ID NO: 1016, wherein said variant induces Tcells cross-reacting with said peptide, or a pharmaceutical acceptablesalt thereof, wherein said peptide is not the underlying full-lengthpolypeptide.

The present invention further relates to a peptide of the presentinvention comprising a sequence that is selected from the group SEQ IDNO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO:543 to SEQ ID NO: 1016 or a variant thereof, which is at least 80%,preferably at least 90%, homologous (preferably at least 80% or at least90% identical) to SEQ ID NO: 1 to SEQ ID NO: 225 or SEQ ID NO: 543 toSEQ ID NO: 1016, wherein said peptide or variant thereof has an overalllength for SEQ ID NO: 1 to SEQ ID NO: 225 of between 8 and 100,preferably between 8 and 30, and most preferred of between 8 and 14amino acids, and for SEQ ID NO: SEQ ID NO: 543 to SEQ ID NO: 1016 ofbetween 12 and 100, preferably between 12 and 30, and most preferred ofbetween 12 to 18 amino acids.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1a -11 depict embodiments as described herein.

FIG. 3a shows the peptides YGYDNVKEY (SEQ ID NO: 21), AVFDGAQVTSK (SEQID NO: 82), SSSGLHPPK (SEQ ID NO: 77), ILDEKPVII (SEQ ID NO: 63),YLNKEIEEA (SEQ ID NO: 44), SILEDPPSI (SEQ ID NO: 213), DLDVKKMPL (SEQ IDNO: 78), QLLDQVEQI (SEQ ID NO: 199), AAANIIRTL (SEQ ID NO: 13),SPRPPLGSSL (SEQ ID NO: 93), APLQRSQSL (SEQ ID NO: 96), SPTSSRTSSL (SEQID NO: 26), KPRQSSPQL (SEQ ID NO: 49), and SASVQRADTSL (SEQ ID NO: 113).

FIG. 4c shows the peptides LPSQAFEYILYNKG (SEQ ID NO: 561),RVEYHFLSPYVSPK (SEQ ID NO: 554), NSVIIVDKNGRLV (SEQ ID NO: 552),DIMRVNVDKVLERDQKL (SEQ ID NO: 831), YKAFSSLLASSAVSPE (SEQ ID NO: 651),and VDKVLERDQKLSELDDR (SEQ ID NO: 821).

FIG. 5a shows the peptides KITVPASQK (SEQ ID NO: 145), SPRASGSGL (SEQ IDNO: 100), SPTSSRTSSL (SEQ ID NO: 26), SPAPRTAL (SEQ ID NO: 202),TPSSRPASL (SEQ ID NO: 205), and RPKNLMQTL (SEQ ID NO: 36).

FIG. 5b shows the peptides VPVPHTTAL (SEQ ID NO: 84), GPRPITQSEL (SEQ IDNO: 203), and KLYELHVFTF (SEQ ID NO: 42).

FIG. 5c shows the peptides TFGERVVAF (SEQ ID NO: 143) and KFAEEFYSF (SEQID NO: 20).

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The following tables show the peptides according to the presentinvention, their respective SEQ ID NO:, and the prospective source(underlying) proteins for these peptides. All peptides in Table 1a and 1b bind to HLA A HLA B or HLA C alleles, peptides in Table 2 bind toHLA-DR alleles (MHC class II). The peptides in table 3 are furtheruseful in the diagnosis and/or treatment of CLL, Acute myelogenousleukemia (AML), and other hematological malignancies, which involve anover-expression or over-presentaion of the respective underlyingpolypeptide.

Thus, the present invention relates in particular to a peptide of thepresent invention comprising a sequence according to SEQ ID NO: 543 toSEQ ID NO: 1016 or a variant thereof, which is at least 80%, preferablyat least 90%, homologous (preferably at least 80% or at least 90%identical) to SEQ ID NO: 543 to SEQ ID NO: 1016, wherein said peptide orvariant thereof has an overall length of between 12 and 100, preferablybetween 12 and 30, and most preferred of between 12 to 18 amino acids.The present invention relates in particular to a peptide of the presentinvention consisting of the sequence according to SEQ ID NO: 543 to SEQID NO: 1016.

TABLE 1a Preferred 49 HLA class I ligandome derived tumor associatedantigens (LiTAAs) according to the invention found represented in ≥20%of CLL patient ligandomes (n = 30) and the 225 representing HLA ligands(LiTAPs) annotated with respective HLA restriction. Number of positiveCLLs SEQ (frequency ID NO: Underlying source protein/HLA ligands [%])HLA APOBEC3D apolipoprotein B mRNA 13 (43.3) editing enzyme, catalyticpolypeptide-like 3D 1 AEHPNVTLTI 1 B*40 2 FLAEHPNVTL 8 A*02 3 ILYGRSYTW1 A*32 4 EVAEFLARH 2 A*26 5 RHSNVNLTI 1 C*07 CDK14 cyclin-dependentkinase 14 12 (40.0) 6 HPDNVKLFL 1 B*35 7 ISDTGELKL 1 C*05 8 KVNGKLVALK 1A*03 9 NRLSAQAAL 1 B*39 10 TPFTAIREA 1 B*55 11 FGLARAKSV 6 B*08 12KIADFGLAR 1 A*03 RASGRF1 Ras protein-specific guanine 12 (40.0)nucleotide-releasing factor 1 13 AAANIIRTL 8 B*35 A*02, B*13, B*51 14GRFKNLREAL 1 B*27 15 MSPFSKATL 2 C*14 16 QEDPGDNQITL 1 B*40 17 SPFSKATL2 B*08, B*07 CDCA7L cell division cycle associated 11 (36.7) 7-like 18DALLKRTM 1 B*08 19 GEDVRSALL 3 B*40 20 KFAEEFYSF 2 A*24 21 YGYDNVKEY 7C*03, C*12 CELSR1 cadherin, EGF LAG seven-pass G- 11 (36.7) typereceptor 1 22 LEVEERTKPV 1 B*44 23 RDSPINANLRY 1 B*40 24 RPFVIVTA 1 B*5525 RPIINTPMV 1 B*55 26 SPTSSRTSSL 7 B*07 27 ATSAPLVSR 1 A*11 AKAP2 Akinase (PRKA) anchor protein 2 11 (36.7) 28 AELRSTASLL 1 B*40 29APASSHERASM 2 B*07 30 ASRQAPPHI 1 A*30 31 AVKKNPGIAA 2 A*02 32EEHLESHKKY 2 B*44 33 GEFTSARAV 1 B*49 34 GQSTPRLFSI 1 B*13 35 LVDDPLEY 1A*01 36 RPKNLMQTL 3 B*07 37 RQAPPHIEL 2 B*13 38 SEAAELRSTA 1 B*50 CTDP1CTD phosphatase, subunit 1 11 (36.7) 39 AAVRIGSVL 2 A*02, B*13 40ERAGVVREL 1 C*07 41 GAAVRIGSVL 1 A*02 42 KLYELHVFTF 1 A*32 43 LYELHVFTF2 A*24, A*23 44 YLNKEIEEA 6 A*02 DNMBP dynamin binding protein 10 [33.3]45 DELPKFHQY 2 B*18 46 DVTGQFPSSF 1 A*26 47 EHSRVLQQL 2 B*39:01 48IKVSKQLL 1 B*08 49 KPRQSSPQL 3 B*07 50 KQLLAALEI 1 B*13 51 RRKDLVLKY 2B*27 52 RTRDYASLPPK 1 A*03 TAGAP T-cell activation RhoGTPase 10 (33.3)activating protein 53 APGSVLPRAL 3 B*07 54 DIKEHPLL 1 B*08 55 DSAGPQDAR1 A*68 56 FQYAKESYI 1 B*13 57 KVLSWPFLM 1 A*32 58 LENDQSLSF 1 B*44 59SPSRQPQV 1 B*07 60 SRHQSFTTK 3 B*27 61 SSHNASKTL 2 C*12 ABCA6ATP-binding cassette, sub-family A 10 (33.3) (ABC1), member 6 62EEIDTTMRW 1 B*44 63 ILDEKPVII 5 A*02 64 LPQEPRTSL 2 B*07 65 LTYKLPVA 1B*57 66 NEMELAHSSF 2 B*18 67 REFPEANFEL 1 B*40 68 THHIPDAKL 1 B*38 69TVKENLSLF 1 A*26 70 VLLKKAVL 1 B*08 DMXL1 Dmx-like 1 10 (33.3) 71HLKSIPVSL 2 B*08, B*07 72 KVWYNVENW 1 A*32 73 LPAYRAQLL 1 B*07 74LSEQTSVPL 1 A*02 75 SLNQWLVSF 1 A*32 76 SMTSLAQKI 1 A*02 77 SSSGLHPPK 2A*03, A*11, A*68 PARP3 poly (ADP-ribose) polymerase 10 (33.3) family,member 3 78 DLDVKKMPL 4 B*08 79 FYTVIPHNF 3 A*24 80 HHINTDNPSL 2 B*39 81RVGEVGQSK 2 A*03 TP53I11 tumor protein p53 inducible protein  8 (26.7)11 82 AVFDGAQVTSK 7 A*03, A*11 83 SQTDLVSRL 1 B*15 B4GALT1UDP-Gal:betaGlcNAc beta 1,4-  8 (26.7) galactosyltransferase,polypeptide 1 84 VPVPHTTAL 7 B*07 85 YQVLDVQRY 1 B*15 IRF9 interferonregulatory factor 9  8 (26.7) 86 APFQGDQRSL 2 B*07 87 DVAEPYKVY 1 A*2688 IVSGQPGTQK 3 A*03 89 TPEQQAAIL 1 B*35 90 VELFRTAYF 1 B*37 KDM2Blysine (K)-specific demethylase 2B  8 (26.7) 91 EHADDDPSL 1 B*38 92SEESVKSTTL 2 B*40 93 SPRPPLGSSL 4 B*07 94 SPWWRSSL 1 B*07 95 VYTPVDSLVF1 A*24 TBC1D22A TBC1 domain family, 8 (26.7) member 22A 96 APLQRSQSL 6B*07, B*08 97 DEVHQDTY 1 B*18 98 LPHSATVTL 1 B*07 ZNF296 zinc fingerprotein 296  8 (26.7) 99 SEAPEAPLL 1 B*40 100 SPRASGSGL 6 B*07 101VVGPAAEAK 2 A*03 BACH2 BTB and CNC homology 1, basic  8 (26.7) leucinezipper transcription factor 2 102 FSITKSVEL 4 A*02 103 GQTKNDLVV 1 B*13104 LSQEVCRD 2 n.a. 105 RDIQSPEQI 1 B*40 106 REDNSSNSL 1 B*40 107TEHQEPGL 2 B*40 108 TKNDLVVSL 1 B*39 PRR12 proline rich 12  8 (26.7) 109AEEAGGTRL 1 B*40 110 ENVNKKDY 1 A*26 111 GLDPNKPPEL 4 A*02 112RPAGEPYNRKTL 2 B*07 ZFAND5 zinc finger, AN1-type domain 5  7 (23.3) 113SASVQRADTSL 5 C*03 114 YGNPRTNGM 2 B*08 ATP5G1 ATP synthase, H+transporting,  7 (23.3) mitochondrial Fo complex, subunit C1 115LIRPVSASF 3 B*07 116 SPVNSSKQPSY 3 B*35 117 QLFSYAILGF 1 A*32 DMDdystrophin  7 (23.3) 118 DEHLLIQHY 2 B*18 119 KQVASSTGF 1 B*15 120RDFGPASQHFL 1 B*40 121 RQLGEVASF 2 A*32 122 TEAETTANVL 1 B*40 123GYLPVQTVL 1 A*24 ARID5B AT rich interactive domain  7 (23.3) 5B(MRF1-like) 124 GQKEALLKY 1 B*15 125 KPSEERKTI 1 B*07 126 KQTPKVLVV 1B*13 127 SVIQHVQSF 1 A*26 128 TPIERIPYL 3 B*51 ZNF638 zinc fingerprotein 638  7 (23.3) 129 AEVEKNETV 1 B*40 130 EVKEEIPLV 1 B*08 131KPTSARSGL 2 B*07 132 KYIETTPLTI 1 A*24 133 SEIKTSIEV 1 B*40 134SVKPTSATK 4 A*03 135 YPNKGVGQA 1 B*55 DDX46 DEAD (Asp-Glu-Ala-Asp) box 7 (23.3) polypeptide 46 136 ISMKILNSL 2 A*02 137 KTIAFLLPMF 1 A*32 138RDSIINDF 2 B*37 139 SVKGGGGNEK 1 A*03 140 GIAKTGSGK 1 A*03 RRM2Bribonucleotide reductase M2  7 (23.3) B (TP53 inducible) 141 AETTDNVFTL1 B*40 142 SEYQRFAVM 3 B*37, B*40, B*49 143 TFGERVVAF 1 A*24 144NENLVERF 2 B*18 BLNK B-cell linker  7 (23.3) 145 KITVPASQK 1 A*03 146KITVPASQKL 7 A*02 147 VPASQKLRQL 2 B*07 HSH2D hematopoietic SH2 domain 7 (23.3) containing 148 HVGYTLSYK 1 A*03 149 KLPLPLPPRL 3 C*14 150KPIEPRREL 1 B*07 151 SHSHVGYTL 3 B*38, B*39 ERP44 endoplasmic reticulumprotein 44  7 (23.3) 152 APSEYRYTL 1 B*07 153 APSEYRYTLL 3 B*07 154EIFQNEVAR 1 A*68 155 KDVLIPGKL 1 B*40 156 VPLVREITF 2 B*08 METTL7Amethyltransferase like 7A  7 (23.3) 157 DPNPNFEKF 1 B*35 158 IQAPLSWEL 1B*13 159 VIYNEQMASK 3 A*03 160 VLRPGGAFY 2 B*15 ELP3 elongatoracetyltransferase complex  7 (23.3) subunit 3 161 EDPDQDILI 1 B*18 162HGNLRELAL 3 B*08 163 KLYPTLVIR 4 A*03 164 SEETFRFEL 1 B*40 NLRP2 NLRfamily, pyrin domain  6 (20.0) containing 2 165 ELNKLLEEI 3 A*02 166IPFSNPRVL 2 B*07 167 LLDEGAKLLY 2 A*01 168 SPADAHRNL 1 B*07 ZC3H12D zincfinger CCCH-type containing  6 (20.0) 12D 169 AELERQAVL 1 B*37 170GRVPGPLSL 1 B*27 171 SDLARLILL 1 B*27 172 TPIREQHVL 3 B*35 NELFEnegative elongation factor complex  6 (20.0) member E 173 APRKGNTL 1B*07 174 EEEEALQKKF 1 B*44 175 KENLVDGF 2 B*37 176 VYKENLVDGF 2 A*23,A*24 ATP6V1C1 ATPase, H+ transporting,  6 (20.0) lysosomal 42 kDa, V1subunit C1 177 TLLVVVPKL 6 A*02 HLA-DMA major histocompatibility  6(20.0) complex, class II, DM alpha 178 HEIDRYTAI 1 B*40 179 VFTLKPLEF 3A*23, A*24 180 YWVPRNAL 2 B*08 TUFM Tu translation elongation factor,  6(20.0) mitochondrial 181 IGVEHVVVY 5 C*12 182 RDKPHVNV 1 B*37 EIF6eukaryotic translation initiation factor 6  6 (20.0) 183 ADVLKVEVF 2B*37 184 IPVVHASI 1 B*51 185 RDSLIDSLT 1 B*40 186 TVADQVLVGSY 2 A*26CKAP4 cytoskeleton-associated protein 4  6 (20.0) 187 AADTERLAL 1 A*02188 DMKAKVASL 2 B*08 189 HVLEEVQQV 2 B*13 190 KEAADTERL 1 B*40 191RISEVLQKL 1 A*02 192 TEVRELVSL 2 B*40 COBLL1 cordon-bleu WH2 repeat  6(20.0) protein-like 1 193 AIRSGEAAAK 2 A*03 194 APNPAPKEL 4 B*07 195RQSLLTAI 1 B*13 196 SPEQTLSPL 1 B*35 197 TEHQVPSSV 1 B*40 198 TTYKIVPPK1 A*03 TMED4 transmembrane emp24 protein  6 (20.0) transport domaincontaining 4 199 QLLDQVEQI 4 A*02 200 DETMVIGNY 1 B*18 201 RQYGSEGRFTF 1B*37 TNFRSF13C tumor necrosis factor receptor  6 (20.0) superfamily,member 13C 202 SPAPRTAL 6 B*07 UBL7 ubiquitin-like 7  6 (20.0) 203GPRPITQSEL 6 B*07 204 KPEPVDKVA 1 B*07 205 TPSSRPASL 4 B*07 CXorf21chromosome X open reading frame  6 (20.0) 21 206 DETQVRSLY 2 B*18 207KEEETNSVATL 1 B*40 208 LEQKVVELY 2 B*18 209 NPISNAVLNEY 1 B*35 210SIKEKSSL 1 B*08 211 TEITEISTPSL 1 B*40 ASUN asunder spermatogenesisregulator  6 (20.0) 212 GRLNSVNNR 1 B*27 213 SILEDPPSI 3 A*02 214TPRTNNIEL 2 B*07 RSL24D1 ribosomal L24 domain containing 1  6 (20.0) 215DAMKRVEEI 3 B*08 216 DIKEVKQNI 3 B*08 217 GPIYPGHGM 1 B*07 Q9UII5,ZNF107 zinc finger protein 107  6 (20.0) 218 GDYGRAFNL 2 B*37 219TRHKIVHTK 2 B*27 220 RIHTGEKPYK 1 A*03 221 KAFNWFSTL 1 A*32 TRAF3IP3TRAF3 interacting protein 3  6 (20.0) 222 QSTQRSLAL 2 B*08 223RDLQMNQALRF 1 B*40 224 RELESQLHVL 2 B*40 225 SEAEKLTLV 1 B*40

TABLE 1b Additional peptides according to the invention for CLL - MHCclass I SEQ ID NO: Amino acid sequence HLA 226 AAAKPVATK A*03, A*11 227ATYHGSFSTK A*03, A*11 228 FMYDRPLRL A*02 229 FRVGNVQEL 230 GVAPFTIARA*03, A*11, A*68 231 KMKPLDGSALY A*30 232 KPAPAKPVA B*55 233 KPVAAKPAAn.a. 234 KQFGVAPFTI B*13 235 QEELVKISL B*40:01 236 RQLGTVQQVI B*13 237RQLINALQI B*13, A*32 238 RVIGGLLAGQTY B*15:01 239 SENAFYLSP n.a. 240SQAPVLDAI B*13 241 STRYPPPAV A*30 242 TEDTLKVYL B*40:01, B*52 243VAAKPVATK A*03 244 VQRVVESL B*08 245 VRNPSVVVK B*27 246 GESEVAIKI B*49,B*52 247 LIYSVGLLLA A*02 248 SAYPHQLSF A*32 249 SVIGVFITK A*03, A*11,A*68 250 AELGNSVQLI B*49 251 ANMTVTRI n.a 252 ARISNVEFY C*07 253AVFIGNQQF B*15:01 254 DIELQAENI A*02 255 DSYTVRVSV B*51 256 DVKIFVNTIB*51 257 EIIPKYGSI A*25 258 EQSKIFIHR n.a 259 FVDVGLYQY A*03 260GHTSTISTL B*39 261 GRIEYVEVF C*07 262 GTSIIPFQK A*11 263 HPFLRGIGY B*35264 IPVEIHTA B*55 265 KIFVNTIAY B*15:01 266 LPEDKVRIAY B*35 267LPFSEGLTV B*51 268 LPWANKVTI B*51 269 PWANKVTI n.a. 270 QAYNRAVTI B*51271 RSFPQKMAY B*15:01 272 RYPIHWHLL C*07 273 SPQNLRLML B*07 274SYFSSPTQR B*27 275 VQIKSSLI B*13 276 VYIGHTSTI C*07 277 YHVPGTGESY C*07278 ATNGDLASR A*31 279 GLHAEVTGVGY B*15:01 280 HVSSTSSSF A*32 281LQADLQNGL B*13 282 SELPVSEVA B*45 283 SQTKSVFEI B*13 284 THIFTSDGL B*39285 VIYFPPLQK A*11 286 YPFSSEQKW B*35 287 GQYFGELAL B*13 288 RIIVKNNAKn.a. 289 RRIIVKNNAK B*27 290 SFGELALMY n.a. 291 AFNAPVINR B*27 292IMKRNIATY B*15:01 293 KVVDVIGTK A*11 294 LPFLKSLEF B*07, B*35 295RLKVVDVIGTK A*03 296 TPRAATITA B*07, B*51, B*55 297 KPSEKIQVL B*07 298VPYPVTTTV B*35 299 ASFPPFVEK B*15 300 AFIHISTAY A*29 301 ATFEKIPFER A*11302 KLFEKVKEV A*02 303 SQMPKLEAF B*15:01 304 AVLGQHHNY A*03 305 GPPAHKPRn.a. 306 RVYDVLVLK A*03, A*11 307 LPRPQGITV B*07 308 VLYVGSKTK A*03 309KTKEQVTNV A*11 310 MPVDPDNEAY B*35 311 AEKTKQGVA B*40 312 DIADFFTTR A*68313 HSYLQRQSV C*12 314 KEVTLIEEL B*40:01 315 REDGPGVAL B*40:01 316REDPLPPGL B*40:01 317 SLFGGSQGLRK A*03 318 AEFQRLKQA B*50 319 EVIDGVPGKWA*25 320 IPKAPGKII B*07, B*08, B*55 321 SHNGSAIRY A*32 322 TEVTVVGDKLB*40:01 323 YASVVVKRY A*28 324 ATDLALYIK A*11 325 AYHNWRHAF C*07 326EPLNIKDAY B*35 327 KIAATIISF B*15:01 328 KIFLHIHGL B*71 329 LEVILKKIn.a. 330 SEHPLAQLY B*44 331 VPSAQTLKI B*51 332 AEYRSYVA B*45 333ALAPGRGTLY A*24 334 GPRGTQAAL B*07 335 IEDPGTLHI B*49 336 IEDPGTLHIWB*44 337 RPIPIAVKY B*35 338 VEKLLTNW n.a. 339 FLDPDIGGVAV A*02 340HTAPPENKTW A*30 341 LLDTPVKTQY A*01 342 NAVKDFTSF A*03, A*11 343SGLLQIKKL n.a. 344 YHDKNIVLL B*39 345 SVDPKNYPK A*11, A*03 346 AVGLVLPAKA*11 347 AVGLVLPAKL n.a. 348 ALLEVLSQK A*03 349 HEKQDTLVA B*45 350KELELQIGM B*40:01, B*52 351 MYSDVWKQL A*24 352 RELQDEKAEL B*40:01 353RITDVLDQK A*11 354 EVIKITGLK A*68 355 HHVDITKKL B*39 356 LPFNVKVSV B*51357 TLPRVLEI B*51 358 TVDLPKSPK A*11 359 AEHGLLLTA B*45 360 AQAGALLQVB*13 361 DGGFVLKV B*51 362 IVYPSGKVY B*15:01 363 KLDNQVSKV A*02 364SENVKLFSA B*45 365 VQKLQNII 366 FSTPHGLEV B*51 367 KRFHQKSDM B*27 368KTFGHAVSL A*32 369 SSNLITHSR A*31 370 GVIDGHIYAV A*02 371 IEPAKETTTNVB*40:01, B*44 372 NAPPSEVLL n.a. 373 SIEPAKETTTNV A*02 374 AQSQHNQSLB*13 375 AQSRTNPQV B*13 376 KMHDKVFAY A*03 377 TAKAPLSTV B*51 378IPTRTVAI B*51 379 NHDRKHAV B*39 380 NNHDRKHAV B*08 381 TPGGTRIIY B*35382 EHWPSPETF A*68 383 EIITNTLSF A*25 384 EVRGALMSAF A*25 385 IPRPILVLLB*07 386 LPNKNRDEL B*07 387 QRIPAGAVL B*27 388 AEGPAGGFMVV B*49 389AYYRDAEAY C*07 390 QVNRPLTMR A*03 391 RHSPVFQVY A*32 392 SLPVPNSAYB*15:01 393 TLGPPGTAHLY B*15:01 394 IEPAKETTTNV B*40:01, B*44 395NAPPSEVLL n.a. 396 SIEPAKETTTNV A*02 397 DLYSGLNQR A*68 398 KAKAKPVTRA*31 399 AVLDKAMKAK A*03 400 LELSTPLKI B*49 401 LPLNLDTKY B*35 402TVIYRIQAL A*02 403 DAHIYLNHI B*51 404 NHIEPLKIQL B*39 405 AYRPAVHPR B*27406 LRAPLEHEL n.a. 407 RLFMVLLLK A*03 408 RSPDVLKDF B*15:01 409ETAPGVHKR A*68 410 LYHGYIYTY A*24 411 GQHVATQHF B*15:01 412 LNGQLPNLn.a. 413 LPFPDETHERY B*35 414 LPHNTHRVV B*51 415 VVFDSPRNR A*03 416YPLGRILI B*51 417 KEFAEFVTS B*50 418 VMLDVPIRL A*02 419 VPMTPLRTV B*51420 QIDYKTLVL B*13 421 VEDPTIVRI B*40:01, B*44, B*52 422 IPYQDLPHL B*07423 DTPFLTGHGR A*68 424 EFYRALYI 425 RYYPQILTNK 426 KAYERHVL B*08 427LPSPEFHDY B*35 428 SLYAHPIEH A*03 429 LVREPGSQA B*08 430 RLAGPGSEKYB*15:01 431 SPGAGRNSVL B*07 432 SVQSDQGYISR A*11 433 GVRPPAPSL B*13 434IFSEKPVFV n.a. 435 KASNLLLGF B*58 436 KRYIFADAY n.a. 437 RNLQLSLPR A*31438 EASEPVALR A*68 439 RPKVPDQSV B*07, B*08, B*35 440 VLYENALKL A*02 441EVLDKSQTNY A*25 442 MPSPIPAKY B*35 443 YGIENFTSV B*51 444 ARAAQVFFL B*27445 EHIVPNAEL B*39 446 EAFEFVKQR A*68 447 NHFEGHYQY n.a. 448 DAYPKNPHLB*51 449 DVNIKSTER A*68 450 HINSIKSVF A*31 451 YESEKVGVA B*50 452ENAPTTVSR A*68 453 RFPHLLAHTY C*14 454 TLDGSLHAV A*02 455 RTVLKNLSLLKA*03 456 FEAKVQAI B*49 457 FFEAKVQAI C*12 458 KELQSTFK n.a. 459NVSSRFEEEI A*02 460 EVWNNLGTTK A*68 461 MIFRSGSLI n.a. 462 NHALPLPGFB*39 463 ASVFGTMPLK A*11 464 REFPDRLVGY B*44 465 SVFGTMPLK A*11 466DEMRFVTQI n.a. 467 ETVHFATTQW A*25 468 LPPPATQI B*51 469 LARDLYAF C*03,C*12 470 LPGIGLSTSL B*53 471 MEVILPML n.a. 472 AILDYILAK A*03 473KIASQLSKL A*02 474 KVTSTTTVK A*03, A*11 475 YNTLLPYTF n.a. 476 FLDPRPLTVA*02 477 SAFADRPAF C*03 478 AAVPVIISR A*68 479 EEIGKVAAA B*45 480FLKDLVASV A*02 481 VIISRALEL C*03 482 APRTTGTPRTSL B*07 483 ESVGGSPQTKA*68 484 IPKDKAIL B*08 485 LPAYGRTTL B*07 486 HQAAIVSKI B*13 487QAAIVSKI B*51 488 RQKMPEDGL B*13 489 SVQKSSGVK A*11 490 DSIGSTVSSER A*68491 LPYNNKDRDAL B*07 492 IYDEIQQEM C*14 493 AQAKGLIQV B*13 494 EVSSEIYQWA*25 495 KWNPVPLSY A*29 496 NRLLAQQSL B*27 497 APRPVAVAV B*07 498FYRETVQVGR A*33 499 LLAPRPVAV A*02 500 GLAALVILK A*03 501 KIQEVFSSYB*15:01 502 ASLDKFLSH A*11 503 ALYATKTLR A*03 504 MEYVISRI n.a. 505VPVGRQPII B*51 506 KLLIGVIAAV A*02 507 LPSLIKLD n.a. (B*51!!) 508PSLIKLDL n.a. 509 ARNKELIGK B*27 510 AVKSNAAAY B*15:01 511 EVIIPHSGWA*25 512 SVKEQEAQF B*15:01 513 APRGLEPIAI B*07 514 GRFGGVITI B*27 515PVAGFFINR A*68 516 TPKTPSRDA B*08, B*55 517 VLFGGKVSGA A*02 518AEHIESRTL B*40, B*44 519 DQYPYLKSV C*12 520 IARNLTQQL B*07 521 IESRTLAIAB*50 522 MTSALPIIQK A*11 523 SLLTSSKGQLQK A*03 524 TSALPIIQK A*11, A*03525 VRLGSLSTK B*27 526 RINEFSISSF B*15 527 DEKQQHIVY B*18 528 DEVYQVTVYB*18 529 GEISEKAKL B*40 530 YTMKEVLFY A*03 531 SQLTTLSFY B*15 532LEKQLIEL B*44 533 ELTLGEFLK A*68, A*33 534 LTLGEFLK A*68 535 LTLGEFLKLA*02 536 TLGEFLKL A*02 537 ITARPVLW B*58 538 KLMSPKLYVW A*32 539KVSAVTLAY A*03 540 VEGSGELFRW B*44 541 RPKSNIVL B*07 542 RPKSNIVLL B*07

TABLE 1c Additional peptides according to the invention for CLL - MHCclass II SEQ ID NO: Amino acid sequence MHC 543 GEPLSYTRFSLARQ class II544 GEPLSYTRFSLARQVD class II 545 GEPLSYTRFSLARQVDG class II 546GGEPLSYTRFSLARQVD class II 547 GGEPLSYTRFSLARQVDG class II 548NPGGYVAYSKAATVTG class II 549 NPGGYVAYSKAATVTGK class II 550NPGGYVAYSKAATVTGKL class II 551 NSVIIVDKNGRL class II 552 NSVIIVDKNGRLVclass II 553 NSVIIVDKNGRLVY class II 554 RVEYHFLSPYVSPK class II 555RVEYHFLSPYVSPKE class II 556 RVEYHFLSPYVSPKESPF class II 557SPFRHVFWGSGSHTL class II 558 SVIIVDKNGRLV class II 559 VEYHFLSPYVSPKclass II 560 VEYHFLSPYVSPKE class II 561 LPSQAFEYILYNKG class II 562LPSQAFEYILYNKGI class II 563 LPSQAFEYILYNKGIM class II 564LPSQAFEYILYNKGIMG class II 565 MNGYFLIERGKNM class II 566 NGYFLIERGKNMclass II 567 PSQAFEYILYNKG class II 568 PSQAFEYILYNKGI class II 569PSQAFEYILYNKGIM class II 570 EGVQYSYSLFHLM class II 571 EGVQYSYSLFHLMLclass II 572 GVQYSYSLFHLM class II 573 GVQYSYSLFHLML class II 574SIISIHPKIQEHQPR class II 575 SSIRTSTNSQVDK class II 576 VLVGYKAVYRISclass II 577 YSSIRTSTNSQVDK class II 578 GGGYGSGGGSGGYGSRRF class II 579GGSFGGRSSGSP class II 580 KGGSFGGRSSGSP class II 581SGQQQSNYGPMKGGSFGGRSSGSPY class II 582 SGSPYGGGYGSGGGSGGYGSRRF class II583 SPYGGGYGSGGGSGGYGSRRF class II 584 YGGGYGSGGGSGGYGSRRF class II 585GNRINEFSISSF class II 586 HGNQITSDKVGRKV class II 587 IPPVNTNLENLYLQclass II 588 LQVLRLDGNEIKR class II 589 LQVLRLDGNEIKRS class II 590LQVLRLDGNEIKRSA class II 591 LRELHLDHNQISRVPN class II 592LYVRLSHNSLTNNG class II 593 VPSRMKYVYFQNNQ class II 594 VPSRMKYVYFQNNQITclass II 595 VPSRMKYVYFQNNQITS class II 596 WIALHGNQITSD class II 597WIALHGNQITSDK class II 598 ADDNVSFRWEALGNT class II 599 ADDNVSFRWEALGNTLclass II 600 DADDNVSFRWEALGNTL class II 601 DDNVSFRWEALGNT class II 602DDNVSFRWEALGNTL class II 603 DNVSFRWEALGNT class II 604 DNVSFRWEALGNTLclass II 605 DNVSFRWEALGNTLS class II 606 DTGSYRAQISTKTSAK class II 607DTGSYRAQISTKTSAKL class II 608 DTITIYSTINHSK class II 609EDTGSYRAQISTKTSAK class II 610 ENDTITIYSTINHSK class II 611ENDTITIYSTINHSKESKPT class II 612 GSYRAQISTKTSAK class II 613NDTITIYSTINH class II 614 NDTITIYSTINHS class II 615 NDTITIYSTINHSKclass II 616 NVSFRWEALGNTL class II 617 SPTNNTVYASVTHSNRET class II 618TGSYRAQISTKTSAK class II 619 TPRENDTITIYSTINHSK class II 620TPRENDTITIYSTINHSKESKPT class II 621 VSFRWEALGNTL class II 622APIHFTIEKLELNEK class II 623 DAQFEVIKGQTIE class II 624 DAQFEVIKGQTIEVRclass II 625 ESYFIPEVRIYDSGT class II 626 IPEVRIYDSGTY class II 627KDKAIVAHNRHGNK class II 628 KDKAIVAHNRHGNKA class II 629 NFVILEFPVEEQDRclass II 630 SQPRISYDAQFEVIK class II 631 SQPRISYDAQFEVIKG class II 632YDAQFEVIKGQTIE class II 633 GNPAYRSFSNSLSQ class II 634 GPPGEAGYKAFSSLLAclass II 635 GPPGEAGYKAFSSLLASS class II 636 GPPGEAGYKAFSSLLASSA classII 637 GPPGEAGYKAFSSLLASSAVSPE class II 638 GPPGEAGYKAFSSLLASSAVSPEKclass II 639 GYKAFSSLLASSAVSP class II 640 GYKAFSSLLASSAVSPE class II641 KAFSSLLASSAVSPE class II 642 NPAYRSFSNSLSQ class II 643SRDDFQEGREGIVAR class II 644 SSSSFHPAPGNAQ class II 645 VARLTESLFLDLclass II 646 VARLTESLFLDLLG class II 647 VIAGNPAYRSFSN class II 648VPQPEPETWEQILRRNVLQ class II 649 YKAFSSLLASSAVS class II 650YKAFSSLLASSAVSP class II 651 YKAFSSLLASSAVSPE class II 652GNQVFSYTANKEIRTDD class II 653 IEEIVLVDDASERD class II 654IEEIVLVDDASERDF class II 655 LENIYPDSQIPRH class II 656 LENIYPDSQIPRHYclass II 657 NQVFSYTANKEIR class II 658 NQVFSYTANKEIRT class II 659NQVFSYTANKEIRTDD class II 660 VHSVINRSPRHMIEE class II 661 EYVSLYHQPAAMclass II 662 IKAEYKGRVTLKQYPR class II 663 LNVHSEYEPSWEEQP class II 664LPYLFQMPAYASSS class II 665 LPYLFQMPAYASSSK class II 666 NFIKAEYKGRVTclass II 667 TNFIKAEYKGRVT class II 668 TTNFIKAEYKGRVT class II 669VTLNVHSEYEPSWEEQP class II 670 YPRKNLFLVEVTQLTESDS class II 671YPRKNLFLVEVTQLTESDSG class II 672 ADLSSFKSQELN class II 673ADLSSFKSQELNER class II 674 ADLSSFKSQELNERN class II 675ADLSSFKSQELNERNE class II 676 ADLSSFKSQELNERNEA class II 677AEQQRLKSQDLELSWNLNG class II 678 EQQRLKSQDLELSWN class II 679ISQELEELRAEQQR class II 680 ISQELEELRAEQQRLK class II 681 KGTKQWVHARYAclass II 682 QADLSSFKSQELNER class II 683 SWNLNGLQADLSSFK class II 684TGSWIGLRNLDLKG class II 685 FGNYNNQSSNFGPMKGGNFGGRS class II 686FGPMKGGNFGGRSSGPYGGGGQY class II 687 GPMKGGNFGGRSSGP class II 688GPYGGGGQYFAKP class II 689 KGGNFGGRSSGP class II 690 NDFGNYNNQSSNFGPclass II 691 SGPYGGGGQYFAKP class II 692 DAGSYKAQINQRNFE class II 693DAGSYKAQINQRNFEVT class II 694 DGELIRTQPQRLPQ class II 695 GELIRTQPQRLPQclass II 696 NPSDGELIRTQPQRLP class II 697 NPSDGELIRTQPQRLPQ class II698 NPSDGELIRTQPQRLPQL class II 699 ASNDMYHSRALQVVR class II 700ASNDMYHSRALQVVRA class II 701 EGVRRALDFAVGEYN class II 702EGVRRALDFAVGEYNK class II 703 SNDMYHSRALQVVR class II 704 VGEYNKASNDMYHclass II 705 VRARKQIVAGVNY class II 706 VRRALDFAVGEYNKASND class II 707VVRARKQIVAGVN class II 708 VVRARKQIVAGVNY class II 709 APLEGARFALVREDclass II 710 APVELILSDETLPAPE class II 711 ELILSDETLPAPE class II 712LAPLEGARFALVRE class II 713 LAPLEGARFALVRED class II 714RGEKELLVPRSSTSPD class II 715 ASKTFTTQETITNAET class II 716DQHFRTTPLEKNAPV class II 717 NTPILVDGKDVMPE class II 718 NTPILVDGKDVMPEVclass II 719 NTPILVDGKDVMPEVN class II 720 SNTPILVDGKDVMPE class II 721SNTPILVDGKDVMPEVN class II 722 TPILVDGKDVMP class II 723 TPILVDGKDVMPEclass II 724 TPILVDGKDVMPEV class II 725 TPILVDGKDVMPEVN class II 726GPLKFLHQDIDSGQG class II 727 GPLKFLHQDIDSGQGIR class II 728LGDIYFKLFRASG class II 729 TGHLFDLSSLSGRAG class II 730 VPSPVDCQVTDLAGNEclass II 731 DGLNSLTYQVLDVQRYPL class II 732 HPVLQRQQLDYGIY class II 733LNSLTYQVLDVQR class II 734 LNSLTYQVLDVQRYP class II 735 LNSLTYQVLDVQRYPLclass II 736 LPQLVGVSTPLQG class II 737 LPQLVGVSTPLQGG class II 738LPQLVGVSTPLQGGS class II 739 RLPQLVGVSTPLQGGS class II 740SPHKVAIIIPFRNR class II 741 SPHKVAIIIPFRNRQE class II 742SPHKVAIIIPFRNRQEH class II 743 AIVQAVSAHRHR class II 744 ARNFERNKAIKVIclass II 745 ARNFERNKAIKVIIA class II 746 NFERNKAIKVII class II 747NFERNKAIKVIIA class II 748 VAIVQAVSAHRH class II 749 VAIVQAVSAHRHR classII 750 VAIVQAVSAHRHRA class II 751 VAIVQAVSAHRHRAR class II 752EEVITLIRSNQQLE class II 753 EEVITLIRSNQQLEN class II 754IPADTFAALKNPNAML class II 755 LKQLLSDKQQKRQSG class II 756LKQLLSDKQQKRQSGQ class II 757 TPSYVAFTDTER class II 758 TPSYVAFTDTERLclass II 759 EGLYSRTLAGSIT class II 760 EGLYSRTLAGSITTPP class II 761EKWYIPDPTGKFN class II 762 GAIAAINSIQHNTR class II 763 LPILVPSAKKAIclass II 764 LPILVPSAKKAIY class II 765 LPILVPSAKKAIYM class II 766LPILVPSAKKAIYMD class II 767 LPILVPSAKKAIYMDD class II 768VEEGLYSRTLAGSIT class II 769 WEKWYIPDPTGKFN class II 770 YKIVNFDPKLLEclass II 771 YKIVNFDPKLLEG class II 772 YKIVNFDPKLLEGKV class II 773LPEFYKTVSPAL class II 774 VGQFIQDVKNSRST class II 775 VGQFIQDVKNSRSTDclass II 776 VVGQFIQDVKNSRS class II 777 VVGQFIQDVKNSRST class II 778VVGQFIQDVKNSRSTD class II 779 VVGQFIQDVKNSRSTDS class II 780DNGHLYREDQTSPAPG class II 781 DNGHLYREDQTSPAPGLR class II 782EVQVFAPANALPARSE class II 783 GHLYREDQTSPAPG class II 784LPARSEAAAVQPVIG class II 785 NGHLYREDQTSPAPG class II 786NGHLYREDQTSPAPGL class II 787 NGHLYREDQTSPAPGLR class II 788VFAPANALPARSEAA class II 789 VQVFAPANALPARSE class II 790 AIVVSDRDGVPVIKclass II 791 GLHAIVVSDRDGVPV class II 792 GLHAIVVSDRDGVPVIK class II 793HAIVVSDRDGVPV class II 794 KLPSVEGLHAIVVSDRDG class II 795LHAIVVSDRDGVPV class II 796 LHAIVVSDRDGVPVI class II 797LHAIVVSDRDGVPVIK class II 798 LPSVEGLHAIVVSDR class II 799 VPVIKVANDNAPEclass II 800 YNTYQVVQFNRLP class II 801 YNTYQVVQFNRLPL class II 802YNTYQVVQFNRLPLV class II 803 YNTYQVVQFNRLPLVV class II 804YYNTYQVVQFNRLP class II 805 YYNTYQVVQFNRLPL class II 806YYNTYQVVQFNRLPLV class II 807 DKIYFMAGSSRKE class II 808DVGTDEEEETAKESTAEKDE class II 809 EVTFKSILFVPTSAP class II 810KSEKFAFQAEVNR class II 811 LPEFDGKRFQNVAK class II 812 DGSYRIFSKGASEclass II 813 GSYRIFSKGASE class II 814 SDGSYRIFSKGASE class II 815SVKKMMKDNNLVRH class II 816 VKKMMKDNNLVRH class II 817 NNMRIFGEAAEKNclass II 818 VDKVLERDQKLSE class II 819 VDKVLERDQKLSELD class II 820VDKVLERDQKLSELDD class II 821 VDKVLERDQKLSELDDR class II 822VLERDQKLSELDDR class II 823 ATRSIQVDGKTIKAQ class II 824ATRSIQVDGKTIKAQI class II 825 IGVEFATRSIQVDGK class II 826 RSIQVDGKTIKAclass II 827 RSIQVDGKTIKAQ class II 828 RSIQVDGKTIKAQI class II 829TRSIQVDGKTIKAQ class II 830 DIMRVNVDKVLERDQK class II 831DIMRVNVDKVLERDQKL class II 832 IMRVNVDKVLERDQK class II 833VDKVLERDQKLSE class II 834 VDKVLERDQKLSELD class II 835 VDKVLERDQKLSELDDclass II 836 VDKVLERDQKLSELDDR class II 837 VLERDQKLSELDDR class II 838ATRSIQVDGKTIKAQ class II 839 ATRSIQVDGKTIKAQI class II 840IGVEFATRSIQVDGK class II 841 RSIQVDGKTIKA class II 842 RSIQVDGKTIKAQclass II 843 RSIQVDGKTIKAQI class II 844 TRSIQVDGKTIKAQ class II 845GIRVAPVPLYNS class II 846 GIRVAPVPLYNSFH class II 847 NPNGIRVAPVPLYNSFHclass II 848 DDPAIDVCKKLLGKYPN class II 849 DKQPYSKLPGVSLLKP class II850 DKQPYSKLPGVSLLKPL class II 851 HPRYYISANVTGFK class II 852SHPRYYISANVTG class II 853 SHPRYYISANVTGFK class II 854 TSHPRYYISANVTGclass II 855 TSHPRYYISANVTGFK class II 856 ADIFVDPVLHTA class II 857ADIFVDPVLHTACA class II 858 DPGADYRIDRALNEA class II 859 IAQDYKVSYSLAclass II 860 IAQDYKVSYSLAK class II 861 ISRDWKLDPVLYRK class II 862LIAQDYKVSYSLA class II 863 RQKLIAQDYKVSYS class II 864 RQKLIAQDYKVSYSLclass II 865 RQKLIAQDYKVSYSLA class II 866 RQKLIAQDYKVSYSLAK class II867 SALDYRLDPQLQLH class II 868 SKADIFVDPVLHTA class II 869SPSKNYILSVISGSI class II 870 ETTQLTADSHPSYHTDG class II 871SGESLYHVLGLDKNATSDD class II 872 TTQLTADSHPSYHT class II 873TTQLTADSHPSYHTD class II 874 TTQLTADSHPSYHTDG class II 875 SVEEFLSEKLERIclass II 876 VEEFLSEKLERI class II 877 DLSSSILAQSRERVA class II 878EKGVRTLTAAAVSGAQ class II 879 EKGVRTLTAAAVSGAQP class II 880EKGVRTLTAAAVSGAQPI class II 881 KGVRTLTAAAVSGA class II 882KGVRTLTAAAVSGAQ class II 883 VGPFAPGITEKAPEEKK class II 884DPPLIALDKDAPLR class II 885 EIITPDVPFTVDKDG class II 886 IITPDVPFTVDKDGclass II 887 PPLIALDKDAPLR class II 888 TNVKKSHKATVHIQ class II 889DDNIKTYSDHPE class II 890 DDNIKTYSDHPEK class II 891 DSAVFFEQGTTRIGclass II 892 GDKVYVHLKNLASRPY class II 893 GDKVYVHLKNLASRPYT class II894 VHLKNLASRPYT class II 895 VYVHLKNLASRPY class II 896 VYVHLKNLASRPYTclass II 897 VYVHLKNLASRPYTFH class II 898 YVHLKNLASRPY class II 899YVHLKNLASRPYT class II 900 YVHLKNLASRPYTFH class II 901 SNLIKLAQKVPTADclass II 902 YDTRTSALSAKS class II 903 ALMTDPKLITWSPV class II 904NDVAWNFEKFLVGPDG class II 905 QSVYAFSARPLAG class II 906QSVYAFSARPLAGGEPV class II 907 WNFEKFLVGPDG class II 908 DVGMFVALTKLGQPDclass II 909 VGMFVALTKLGQPD class II 910 AGVFHVEKNGRY class II 911FAGVFHVEKNGRYS class II 912 GPITITIVNRDGTR class II 913 NGRYSISRTEAADLclass II 914 RKSRQGSLAMEELK class II 915 RRKSRQGSLAMEELK class II 916EEFKKLTSIKIQNDK class II 917 INRRMADDNKLFR class II 918 TATIVMVTNLKERKEclass II 919 ELFYKGIRPAINVG class II 920 GQKRSTVAQLVKR class II 921SDLDAATQQLLSRGV class II 922 FDFSQNTRVPRLPE class II 923 GDAPAILFDKEFclass II 924 VTHEIDRYTAIAY class II 925 GQGYLIKDGKLIKNNA class II 926IDTTSKFGHGRFQTM class II 927 IDVIGVTKGKGYKGVTSRW class II 928MGPLKKDRIAKEEGA class II 929 AAKYQLDPTASISA class II 930 IAAKYQLDPTASISAclass II 931 IAAKYQLDPTASISAK class II 932 AGLGRAYALAFAERG class II 933DAFGRIDVVVNNAG class II 934 GLGRAYALAFAER class II 935 GLGRAYALAFAERGclass II 936 AKFALNGEEFMNFDL class II 937 AKFALNGEEFMNFDLK class II 938ALNGEEFMNFDLK class II 939 KFALNGEEFMNFDL class II 940 SDGSFHASSSLTVKclass II 941 EERNLLSVAYKNVVGAR class II 942 ERNLLSVAYKNVVGAR class II943 IAELDTLSEESYKD class II 944 IAELDTLSEESYKDS class II 945ADSYLDEGFLLDKKIG class II 946 DSYLDEGFLLDKK class II 947 DSYLDEGFLLDKKIGclass II 948 VDNIIKAAPRKRVPD class II 949 SPPQFRVNGAISN class II 950SPPQFRVNGAISNFE class II 951 SPPQFRVNGAISNFEE class II 952SPPQFRVNGAISNFEEF class II 953 VGKMFVDVYFQEDKK class II 954VGKMFVDVYFQEDKKE class II 955 DPKRTIAQDYGVLKADE class II 956DPKRTIAQDYGVLKADEG class II 957 PKRTIAQDYGVLKADEG class II 958GLFIIDDKGILRQ class II 959 GLFIIDDKGILRQIT class II 960 RGLFIIDDKGILRclass II 961 RGLFIIDDKGILRQ class II 962 RGLFIIDDKGILRQIT class II 963GNTVIHLDQALARMR class II 964 NTVIHLDQALARMR class II 965 NTVIHLDQALARMREclass II 966 ENNEIISNIRDSVIN class II 967 NNEIISNIRDSVIN class II 968SPTVQVFSASGKPV class II 969 SSPTVQVFSASGKPVE class II 970AEPNYHSLPSARTDEQ class II 971 SSILAKTASNIIDVS class II 972LEARATAPPAPSAPN class II 973 ADDLEGEAFLPL class II 974 ADDLEGEAFLPLRclass II 975 ADDLEGEAFLPLRE class II 976 GADDLEGEAFLPLR class II 977AGREINLVDAHLKSE class II 978 AGREINLVDAHLKSEQT class II 979GREINLVDAHLKSE class II 980 KPGIVYASLNHSVIG class II 981NKPGIVYASLNHSVIG class II 982 TTLYVTDVKSASERPS class II 983APSTYAHLSPAKTPPP class II 984 APSTYAHLSPAKTPPPP class II 985APSTYAHLSPAKTPPPPA class II 986 RDDLYDQDDSRDFPR class II 987TRPYHSLPSEAVFA class II 988 TRPYHSLPSEAVFAN class II 989 VAVFTFHNHGRTclass II 990 VAVFTFHNHGRTA class II 991 VAVFTFHNHGRTANL class II 992EDDYIKSWEDNQQGDE class II 993 ELERIQIQEAAKKKPG class II 994ERIQIQEAAKKKP class II 995 ERIQIQEAAKKKPG class II 996 ERIQIQEAAKKKPGIclass II 997 LERIQIQEAAKKKPG class II 998 LSSISQYSGKIK class II 999SPAKDSLSFEDF class II 1000 SPAKDSLSFEDFLDL class II 1001 INSRFPIPSATDPDclass II 1002 VQHYELLNGQSVFG class II 1003 DNQYAVLENQKSSH class II 1004GPPEIYSDTQFPS class II 1005 GPPEIYSDTQFPSLQ class II 1006TPQGPPEIYSDTQFPS class II 1007 TPQGPPEIYSDTQFPSLQ class II 1008TPQGPPEIYSDTQFPSLQST class II 1009 ANLQRAYSLAKEQR class II 1010NLQRAYSLAKEQR class II 1011 TPSGITYDRKDIEEH class II 1012 VSTLNSEDFVLVSRclass II 1013 VSTLNSEDFVLVSRQ class II 1014 VSTLNSEDFVLVSRQG class II1015 GSSFFGELFNQNPE class II 1016 SGSSFFGELFNQNPE class II

TABLE 2 Peptides according to the invention suitable for the (combined)treatment of CLL and/or AML SEQ ID NO: Amino acid sequence 710APVELILSDETLPAPE 878 EKGVRTLTAAAVSGAQ 879 EKGVRTLTAAAVSGAQP 533ELTLGEFLK 476 FLDPRPLTV 892 GDKVYVHLKNLASRPY 111 GLDPNKPPEL 178HEIDRYTAI 181 IGVEHVVVY 184 IPVVHASI 882 KGVRTLTAAAVSGAQ 363 KLDNQVSKV42 KLYELHVFTF 163 KLYPTLVIR 137 KTIAFLLPMF 713 LAPLEGARFALVRED 532LEKQLIEL 734 LNSLTYQVLDVQRYP 736 LPQLVGVSTPLQG 737 LPQLVGVSTPLQGG 738LPQLVGVSTPLQGGS 534 LTLGEFLK 535 LTLGEFLKL 914 RKSRQGSLAMEELK 739RLPQLVGVSTPLQGGS 477 SAFADRPAF 164 SEETFRFEL 364 SENVKLFSA 531 SQLTTLSFY536 TLGEFLKL 186 TVADQVLVGSY 179 VFTLKPLEF 159 VIYNEQMASK 365 VQKLQNII895 VYVHLKNLASRPY 44 YLNKEIEEA 180 YWVPRNAL

Thus, particularly preferred is at least one peptide according to thepresent invention selected from the group consisting of SEQ ID NO: 710,878, 879, 533, 476, 892, 111, 178, 181, 184, 882, 363, 42, 163, 137,713, 532, 734, 736, 737, 738, 534, 535, 914, 739, 477, 164, 364, 531,536, 186, 179, 159, 365, 895, 44, and 180, and the use thereof in thetreatment of AML and/or CML as described herein.

The present invention furthermore relates to the peptides according tothe present invention for use in the treatment of CLLAML As shown in thefollowing table 3, many of the peptides according to the presentinvention can also be used in other cancerous and proliferativeindications.

TABLE 3 Peptides according to the present invention and their specificuses in other proliferative diseases, optionally in other organs. Seq IDSequence Tissue and disease 1 AEHPNVTLTI colon or rectum, spleen,non-Hodgkin's lymphoma 2 FLAEHPNVTL colon or rectum, spleen,non-Hodgkin's lymphoma 3 ILYGRSYTW stomach, adenocarcinoma, skin,squamous cell carcinoma 4 EVAEFLARH colon or rectum, spleen,non-Hodgkin's lymphoma 5 RHSNVNLTI colon or rectum, spleen,non-Hodgkin's lymphoma 6 HPDNVKLFL pancreas, adenocarcinoma, non-Hodgkin's lymphoma, small lymphocytic type 7 ISDTGELKL pancreas,adenocarcinoma, non- Hodgkin's lymphoma, small lymphocytic type 8KVNGKLVALK pancreas, adenocarcinoma, non- Hodgkin's lymphoma, smalllymphocytic type 9 NRLSAQAAL pancreas, adenocarcinoma, non- Hodgkin'slymphoma, small lymphocytic type 10 TPFTAIREA pancreas, adenocarcinoma,non- Hodgkin's lymphoma, small lymphocytic type 11 FGLARAKSV kidney,clear cell renal cell carcinoma, 12 KIADFGLAR brain, glioblastoma,liver, hepatocellular carcinoma 13 AAANIIRTL liver, hepatocellularcarcinoma, adrenal gland, adrenal cortical carcinoma 14 GRFKNLREALliver, hepatocellular carcinoma, adrenal gland, adrenal corticalcarcinoma 15 MSPFSKATL liver, hepatocellular carcinoma, adrenal gland,adrenal cortical carcinoma 16 QEDPGDNQITL liver, hepatocellularcarcinoma, adrenal gland, adrenal cortical carcinoma 17 SPFSKATL liver,hepatocellular carcinoma, adrenal gland, adrenal cortical carcinoma 18DALLKRTM stomach, metastatic, skin, basal cell carcinoma 19 GEDVRSALLstomach, metastatic, skin, basal cell carcinoma 20 KFAEEFYSF stomach,metastatic, skin, basal cell carcinoma 21 YGYDNVKEY stomach, metastatic,skin, basal cell carcinoma 22 LEVEERTKPV lung, non-small cell lungcarcinoma, breast, carcinoma 23 RDSPINANLRY lung, non-small cell lungcarcinoma, breast, carcinoma 24 RPFVIVTA lung, non-small cell lungcarcinoma, breast, carcinoma 25 RPIINTPMV lung, non-small cell lungcarcinoma, breast, carcinoma 26 SPTSSRTSSL lung, non-small cell lungcarcinoma, breast, carcinoma 27 ATSAPLVSR stomach, metastatic, lung,neuroendocrine carcinoma (non-small cell type) 28 AELRSTASLL lipoma 29APASSHERASM lipoma 30 ASRQAPPHI lipoma 31 AVKKNPGIAA lipoma 32EEHLESHKKY lipoma 33 GEFTSARAV lipoma 34 GQSTPRLFSI lipoma 35 LVDDPLEYlipoma 36 RPKNLMQTL lipoma 37 RQAPPHIEL lipoma 38 SEAAELRSTA lipoma 39AAVRIGSVL colon, adenoma 40 ERAGVVREL colon, adenoma 41 GAAVRIGSVLcolon, adenoma 42 KLYELHVFTF colon, adenoma 43 LYELHVFTF colon, adenoma44 YLNKEIEEA colon, adenoma 45 DELPKFHQY stomach, adenocarcinoma, whiteblood cell s, chronic lymphocytic leukemia 46 DVTGQFPSSF stomach,adenocarcinoma, white blood cell s, chronic lymphocytic leukemia 47EHSRVLQQL stomach, adenocarcinoma, white blood cell s, chroniclymphocytic leukemia 48 IKVSKQLL stomach, adenocarcinoma, white bloodcell s, chronic lymphocytic leukemia 49 KPRQSSPQL stomach,adenocarcinoma, white blood cell s, chronic lymphocytic leukemia 50KQLLAALEI stomach, adenocarcinoma, white blood cell s, chroniclymphocytic leukemia 51 RRKDLVLKY stomach, adenocarcinoma, liver, focalnodular hyperplasia 52 RTRDYASLPPK stomach, adenocarcinoma, white bloodcell s, chronic lymphocytic leukemia 53 APGSVLPRAL stomach,adenocarcinoma, lymph node, Hodgkin's disease 54 DIKEHPLL stomach,adenocarcinoma, lymph node, Hodgkin's disease 55 DSAGPQDAR stomach,adenocarcinoma, lymph node, Hodgkin's disease 56 FQYAKESYI stomach,adenocarcinoma, lymph node, Hodgkin's disease 57 KVLSWPFLM stomach,adenocarcinoma, lymph node, Hodgkin's disease 58 LENDQSLSF stomach,adenocarcinoma, lymph node, Hodgkin's disease 59 SPSRQPQV stomach,adenocarcinoma, lymph node, Hodgkin's disease 60 SRHQSFTTK stomach,adenocarcinoma, lymph node, Hodgkin's disease 61 SSHNASKTL stomach,adenocarcinoma, lymph node, Hodgkin's disease 62 EEIDTTMRW liver,hepatocellular carcinoma, lipoma 63 ILDEKPVII liver, hepatocellularcarcinoma, lipoma 64 LPQEPRTSL liver, hepatocellular carcinoma, lipoma65 LTYKLPVA liver, hepatocellular carcinoma, lipoma 66 NEMELAHSSF liver,hepatocellular carcinoma, lipoma 67 REFPEANFEL liver, hepatocellularcarcinoma, lipoma 68 THHIPDAKL liver, hepatocellular carcinoma, lipoma69 TVKENLSLF liver, hepatocellular carcinoma, lipoma 70 VLLKKAVL liver,hepatocellular carcinoma, lipoma 71 HLKSIPVSL kidney, clear cell renalcell carcinoma 72 KVWYNVENW kidney, clear cell renal cell carcinoma,prostate, adenocarcinoma 73 LPAYRAQLL kidney, clear cell renal cellcarcinoma, prostate, adenocarcinoma 74 LSEQTSVPL kidney, clear cellrenal cell carcinoma, prostate, adenocarcinoma 75 SLNQWLVSF kidney,clear cell renal cell carcinoma, prostate, adenocarcinoma 76 SMTSLAQKIkidney, clear cell renal cell carcinoma, prostate, adenocarcinoma 77SSSGLHPPK kidney, clear cell renal cell carcinoma, prostate,adenocarcinoma 78 DLDVKKMPL stomach, metastatic, kidney, carcinoma 79FYTVIPHNF stomach, metastatic, kidney, carcinoma 80 HHINTDNPSL stomach,metastatic, kidney, carcinoma 81 RVGEVGQSK stomach, metastatic, kidney,carcinoma 82 AVFDGAQVTSK lung, non-small cell lung carcinoma, kidney,oncocytoma 83 SQTDLVSRL lung, non-small cell lung carcinoma, kidney,oncocytoma 84 VPVPHTTAL kidney, clear cell renal cell carcinoma,endometrium, adenocarcinoma, endometrioid type 85 YQVLDVQRY kidney,clear cell renal cell carcinoma, endometrium, adenocarcinoma,endometrioid type 86 APFQGDQRSL colon or rectum, breast, mucinouscarcinoma 87 DVAEPYKVY colon or rectum, breast, mucinous carcinoma 88IVSGQPGTQK colon or rectum, breast, mucinous carcinoma 89 TPEQQAAILcolon or rectum, breast, mucinous carcinoma 90 VELFRTAYF colon orrectum, breast, mucinous carcinoma 91 EHADDDPSL brain, cancer, kidney,Wilm's tumor 92 SEESVKSTTL brain, cancer, kidney, Wilm's tumor 93SPRPPLGSSL brain, cancer, kidney, Wilm's tumor 94 SPWWRSSL brain,cancer, kidney, Wilm's tumor 95 VYTPVDSLVF brain, cancer, kidney, Wilm'stumor 96 APLQRSQSL pancreas, adenocarcinoma, kidney, renal cellcarcinoma 97 DEVHQDTY pancreas, adenocarcinoma, kidney, renal cellcarcinoma 98 LPHSATVTL pancreas, adenocarcinoma, kidney, renal cellcarcinoma 99 SEAPEAPLL testis, seminoma 100 SPRASGSGL testis, seminoma101 VVGPAAEAK testis, seminoma 102 FSITKSVEL non-Hodgkin's lymphoma,small lymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, smalllymphocytic type 104 LSQEVCRD non-Hodgkin's lymphoma, small lymphocytictype 105 RDIQSPEQI non-Hodgkin's lymphoma, small lymphocytic type 106REDNSSNSL non-Hodgkin's lymphoma, small lymphocytic type 107 TEHQEPGLnon-Hodgkin's lymphoma, small lymphocytic type 108 TKNDLVVSLnon-Hodgkin's lymphoma, small lymphocytic type 109 AEEAGGTRL breast,carcinoma 110 ENVNKKDY breast, carcinoma 111 GLDPNKPPEL breast,carcinoma 112 RPAGEPYNRKTL breast, carcinoma 113 SASVQRADTSL liver,hepatocellular carcinoma, adrenal gland, adrenal cortical adenoma 114YGNPRTNGM stomach, metastatic, breast, carcinoma 115 LIRPVSASFesophagus, adenocarcinoma 116 SPVNSSKQPSY esophagus, adenocarcinoma 117QLFSYAILGF liver, hepatocellular carcinoma, colon, non-Hodgkin'slymphoma 118 DEHLLIQHY liver, hepatocellular carcinoma, parotid gland,pleomorphic adenoma 119 KQVASSTGF liver, hepatocellular carcinoma,parotid gland, pleomorphic adenoma 120 RDFGPASQHFL liver, hepatocellularcarcinoma, parotid gland, pleomorphic adenoma 121 RQLGEVASF liver,hepatocellular carcinoma, parotid gland, pleomorphic adenoma 122TEAETTANVL liver, hepatocellular carcinoma, parotid gland, pleomorphicadenoma 123 GYLPVQTVL kidney, clear cell renal cell carcinoma, parotidgland, pleomorphic adenoma 124 GQKEALLKY liver, hepatocellularcarcinoma, synovial sarcoma 125 KPSEERKTI liver, hepatocellularcarcinoma, synovial sarcoma 126 KQTPKVLVV liver, hepatocellularcarcinoma, synovial sarcoma 127 SVIQHVQSF liver, hepatocellularcarcinoma, synovial sarcoma 128 TPIERIPYL liver, hepatocellularcarcinoma, synovial sarcoma 129 AEVEKNETV kidney, clear cell renal cellcarcinoma, spleen, non-Hodgkin's lymphoma 130 EVKEEIPLV kidney, clearcell renal cell carcinoma, spleen, non-Hodgkin's lymphoma 131 KPTSARSGLkidney, clear cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma132 KYIETTPLTI kidney, clear cell renal cell carcinoma, spleen,non-Hodgkin's lymphoma 133 SEIKTSIEV kidney, clear cell renal cellcarcinoma, spleen, non-Hodgkin's lymphoma 134 SVKPTSATK kidney, clearcell renal cell carcinoma, spleen, non-Hodgkin's lymphoma 135 YPNKGVGQAkidney, clear cell renal cell carcinoma, spleen, non-Hodgkin's lymphoma136 ISMKILNSL lung, non-small cell lung carcinoma, thymus, thymoma,benign 137 KTIAFLLPMF lung, non-small cell lung carcinoma, thymus,thymoma, benign 138 RDSIINDF lung, non-small cell lung carcinoma,thymus, thymoma, benign 139 SVKGGGGNEK lung, non-small cell lungcarcinoma, thymus, thymoma, benign 140 GIAKTGSGK lung, non-small celllung carcinoma, thymus, thymoma, benign 141 AETTDNVFTL kidney, clearcell renal cell carcinoma, thyroid gland, follicular adenoma 142SEYQRFAVM kidney, clear cell renal cell carcinoma, thyroid gland,follicular adenoma 143 TFGERVVAF kidney, clear cell renal cellcarcinoma, thyroid gland, follicular adenoma 144 NENLVERF stomach,adenocarcinoma, colon, adenocarcinoma 145 KITVPASQK stomach,adenocarcinoma, colon, non- Hodgkin's lymphoma 146 KITVPASQKL stomach,adenocarcinoma, colon, non- Hodgkin's lymphoma 147 VPASQKLRQL stomach,adenocarcinoma, colon, non- Hodgkin's lymphoma 148 HVGYTLSYK stomach,adenocarcinoma 149 KLPLPLPPRL stomach, adenocarcinoma 150 KPIEPRRELstomach, adenocarcinoma 151 SHSHVGYTL stomach, adenocarcinoma 152APSEYRYTL colon or rectum, stomach, mucinous adenocarcinoma 153APSEYRYTLL colon or rectum, stomach, mucinous adenocarcinoma 154EIFQNEVAR colon or rectum, stomach, mucinous adenocarcinoma 155KDVLIPGKL colon or rectum, stomach, mucinous adenocarcinoma 156VPLVREITF colon or rectum, stomach, mucinous adenocarcinoma 157DPNPNFEKF liver, hepatocellular carcinoma, cancer, liver, focal nodularhyperplasia 158 IQAPLSWEL liver, hepatocellular carcinoma, cancer,liver, focal nodular hyperplasia 159 VIYNEQMASK liver, hepatocellularcarcinoma, cancer, liver, focal nodular hyperplasia 160 VLRPGGAFY liver,hepatocellular carcinoma, cancer, liver, focal nodular hyperplasia 161EDPDQDILI stomach, adenocarcinoma, endometrium, adenocarcinoma,endometrioid 162 HGNLRELAL stomach, adenocarcinoma, endometrium,adenocarcinoma, endometrioid 163 KLYPTLVIR stomach, adenocarcinoma,endometrium, adenocarcinoma, endometrioid 164 SEETFRFEL stomach,adenocarcinoma, endometrium, adenocarcinoma, endometrioid 165 ELNKLLEEIstomach, adenocarcinoma, ovary, adenocarcinoma, endometrioid 166IPFSNPRVL stomach, adenocarcinoma, ovary, adenocarcinoma, endometrioid167 LLDEGAKLLY stomach, adenocarcinoma, ovary, adenocarcinoma,endometrioid 168 SPADAHRNL stomach, adenocarcinoma, ovary,adenocarcinoma, endometrioid 173 APRKGNTL stomach, metastatic,endometrium, Mullerian mixed tumor 174 EEEEALQKKF stomach, metastatic,endometrium, Mullerian mixed tumor 175 KENLVDGF stomach, metastatic,endometrium, Mullerian mixed tumor 176 VYKENLVDGF stomach, metastatic,endometrium, Mullerian mixed tumor 177 TLLVVVPKL stomach,adenocarcinoma, bone, giant cell tumor of bone 178 HEIDRYTAI kidney,clear cell renal cell carcinoma, non-Hodgkin's lymphoma 179 VFTLKPLEFkidney, clear cell renal cell carcinoma, non-Hodgkin's lymphoma 180YWVPRNAL kidney, clear cell renal cell carcinoma, non-Hodgkin's lymphoma181 IGVEHVVVY brain, cancer, kidney, oncocytoma 182 RDKPHVNV brain,cancer, omentum, leiomyosarcoma 183 ADVLKVEVF stomach, adenocarcinoma,colon, adenocarcinoma 184 IPVVHASI stomach, adenocarcinoma, colon,adenocarcinoma 185 RDSLIDSLT stomach, adenocarcinoma, colon,adenocarcinoma 186 TVADQVLVGSY stomach, adenocarcinoma, colon,adenocarcinoma 187 AADTERLAL lung, non-small cell lung carcinoma,chondrosarcoma 188 DMKAKVASL lung, non-small cell lung carcinoma,chondrosarcoma 189 HVLEEVQQV lung, non-small cell lung carcinoma,chondrosarcoma 190 KEAADTERL lung, non-small cell lung carcinoma,chondrosarcoma 191 RISEVLQKL lung, non-small cell lung carcinoma,chondrosarcoma 192 TEVRELVSL lung, non-small cell lung carcinoma,chondrosarcoma 193 AIRSGEAAAK liver, hepatocellular carcinoma, pleura,malignant mesothelioma 194 APNPAPKEL liver, hepatocellular carcinoma,pleura, malignant mesothelioma 195 RQSLLTAI liver, hepatocellularcarcinoma, liver, hepatocellular carcinoma, cancer, pleura, malignantmesothelioma 196 SPEQTLSPL liver, hepatocellular carcinoma, pleura,malignant mesothelioma 197 TEHQVPSSV liver, hepatocellular carcinoma,liver, hepatocellular carcinoma, cancer, pleura, malignant mesothelioma198 TTYKIVPPK liver, hepatocellular carcinoma, liver, hepatocellularcarcinoma, cancer, pleura, malignant mesothelioma 199 QLLDQVEQI stomach,metastatic thyroid gland, papillary carcinoma 200 DETMVIGNY stomach,metastatic, rectum, adenocarcinoma 201 RQYGSEGRFTF kidney, clear cellrenal cell carcinoma, rectum, adenocarcinoma 203 GPRPITQSEL stomach,metastatic, lymph node, non- Hodgkin's lymphoma 204 KPEPVDKVA stomach,metastatic, lymph node, non- Hodgkin's lymphoma 205 TPSSRPASL stomach,metastatic, lymph node, non- Hodgkin's lymphoma 212 GRLNSVNNR kidney,clear cell renal cell carcinoma, leiomyosarcoma 213 SILEDPPSI kidney,clear cell renal cell carcinoma, leiomyosarcoma 214 TPRTNNIEL kidney,clear cell renal cell carcinoma, leiomyosarcoma 215 DAMKRVEEI stomach,adenocarcinoma, ovary, thecoma-fibroma 216 DIKEVKQNI stomach,adenocarcinoma, ovary, thecoma-fibroma 217 GPIYPGHGM stomach,adenocarcinoma, ovary, thecoma-fibroma 218 GDYGRAFNL stomach,metastatic, lymph node, non- Hodgkin's lymphoma 219 TRHKIVHTK stomach,metastatic, lymph node, non- Hodgkin's lymphoma 220 RIHTGEKPYK colon orrectum, thyroid gland, nodular hyperplasia 221 KAFNWFSTL stomach,metastatic, lymph node, non- Hodgkin's lymphoma 222 QSTQRSLAL liver,hepatocellular carcinoma, uterin cervix, squamous cell carcinoma 223RDLQMNQALRF liver, hepatocellular carcinoma, uterin cervix, squamouscell carcinoma 224 RELESQLHVL liver, hepatocellular carcinoma, uterincervix, squamous cell carcinoma 225 SEAEKLTLV liver, hepatocellularcarcinoma, uterin cervix, squamous cell carcinoma 226 AAAKPVATKpancreas, adenocarcinoma, fibromatosis 227 ATYHGSFSTK pancreas,adenocarcinoma, fibromatosis 228 FMYDRPLRL pancreas, adenocarcinoma,fibromatosis 229 FRVGNVQEL pancreas, adenocarcinoma, fibromatosis 230GVAPFTIAR pancreas, adenocarcinoma, fibromatosis 231 KMKPLDGSALYpancreas, adenocarcinoma, fibromatosis 232 KPAPAKPVA pancreas,adenocarcinoma, fibromatosis 233 KPVAAKPAA pancreas, adenocarcinoma,fibromatosis 234 KQFGVAPFTI pancreas, adenocarcinoma, fibromatosis 235QEELVKISL pancreas, adenocarcinoma, fibromatosis 236 RQLGTVQQVIpancreas, adenocarcinoma, fibromatosis 237 RQLINALQI pancreas,adenocarcinoma, fibromatosis 238 RVIGGLLAGQTY pancreas, adenocarcinoma,fibromatosis 239 SENAFYLSP pancreas, adenocarcinoma, fibromatosis 240SQAPVLDAI pancreas, adenocarcinoma, fibromatosis 241 STRYPPPAV pancreas,adenocarcinoma, fibromatosis 242 TEDTLKVYL pancreas, adenocarcinoma,fibromatosis 243 VAAKPVATK pancreas, adenocarcinoma, fibromatosis 244VQRVVESL pancreas, adenocarcinoma, fibromatosis 245 VRNPSVVVK pancreas,adenocarcinoma, fibromatosis 246 GESEVAIKI myometrium, leiomyoma 247LIYSVGLLLA myometrium, leiomyoma 248 SAYPHQLSF myometrium, leiomyoma 249SVIGVFITK myometrium, leiomyoma 250 AELGNSVQLI liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 251 ANMTVTRI liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 252ARISNVEFY liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 253 AVFIGNQQF liver, hepatocellular carcinoma, thyroidgland, nodular hyperplasia 254 DIELQAENI liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 255 DSYTVRVSV liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 256DVKIFVNTI liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 257 EIIPKYGSI liver, hepatocellular carcinoma, thyroidgland, nodular hyperplasia 258 EQSKIFIHR liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 259 FVDVGLYQY liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 260GHTSTISTL liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 261 GRIEYVEVF liver, hepatocellular carcinoma, thyroidgland, nodular hyperplasia 262 GTSIIPFQK liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 263 HPFLRGIGY liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 264IPVEIHTA liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 265 KIFVNTIAY liver, hepatocellular carcinoma, thyroidgland, nodular hyperplasia 266 LPEDKVRIAY liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 267 LPFSEGLTV liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 268LPWANKVTI liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 269 PWANKVTI liver, hepatocellular carcinoma, thyroid gland,nodular hyperplasia 270 QAYNRAVTI liver, hepatocellular carcinoma,thyroid gland, nodular hyperplasia 271 RSFPQKMAY liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 272 RYPIHWHLL liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 273SPQNLRLML liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 274 SYFSSPTQR liver, hepatocellular carcinoma, thyroidgland, nodular hyperplasia 275 VQIKSSLI liver, hepatocellular carcinoma,thyroid gland, nodular hyperplasia 276 VYIGHTSTI liver, hepatocellularcarcinoma, thyroid gland, nodular hyperplasia 277 YHVPGTGESY liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 278ATNGDLASR pancreas, adenocarcinoma, prostate, benign nodular hyperplasia279 GLHAEVTGVGY pancreas, adenocarcinoma, prostate, benign nodularhyperplasia 280 HVSSTSSSF pancreas, adenocarcinoma, prostate, benignnodular hyperplasia 281 LQADLQNGL pancreas, adenocarcinoma, prostate,benign nodular hyperplasia 282 SELPVSEVA pancreas, adenocarcinoma,prostate, benign nodular hyperplasia 283 SQTKSVFEI pancreas,adenocarcinoma, prostate, benign nodular hyperplasia 284 THIFTSDGLpancreas, adenocarcinoma, prostate, benign nodular hyperplasia 285VIYFPPLQK pancreas, adenocarcinoma, prostate, benign nodular hyperplasia286 YPFSSEQKW pancreas, adenocarcinoma, prostate, benign nodularhyperplasia 287 GQYFGELAL stomach, gastrointestinal stromal tumor (GIST)288 RIIVKNNAK stomach, gastrointestinal stromal tumor (GIST) 289RRIIVKNNAK stomach, gastrointestinal stromal tumor (GIST) 290 SFGELALMYstomach, gastrointestinal stromal tumor (GIST) 291 AFNAPVINR stomach,gastrointestinal stromal tumor (GIST) 292 IMKRNIATY stomach,gastrointestinal stromal tumor (GIST) 293 KVVDVIGTK stomach,gastrointestinal stromal tumor (GIST) 294 LPFLKSLEF stomach,gastrointestinal stromal tumor (GIST) 295 RLKVVDVIGTK stomach,gastrointestinal stromal tumor (GIST) 296 TPRAATITA stomach,gastrointestinal stromal tumor (GIST) 297 KPSEKIQVL lipoma 298 VPYPVTTTVlipoma 299 ASFPPFVEK lipoma 300 AFIHISTAY colon or rectum, colon,adenocarcinoma 301 ATFEKIPFER colon or rectum, colon, adenocarcinoma 302KLFEKVKEV colon or rectum, colon, adenocarcinoma 303 SQMPKLEAF colon orrectum, colon, adenocarcinoma 304 AVLGQHHNY colon or rectum, colon,adenocarcinoma 305 GPPAHKPR spleen, chronic myeloid leukemia 306RVYDVLVLK colon or rectum, colon, adenocarcinoma 307 LPRPQGITV liver,hepatocellular carcinoma, liver, focal nodular hyperplasia 308 VLYVGSKTKbrain, glioblastoma, schwannoma 309 KTKEQVTNV brain, glioblastoma,schwannoma 310 MPVDPDNEAY brain, glioblastoma, schwannoma 311 AEKTKQGVAbrain, glioblastoma, schwannoma 312 DIADFFTTR kidney, clear cell renalcell carcinoma, adrenal gland, adrenal cortical adenoma 313 HSYLQRQSVkidney, clear cell renal cell carcinoma, adrenal gland, adrenal corticaladenoma 314 KEVTLIEEL kidney, clear cell renal cell carcinoma, adrenalgland, adrenal cortical adenoma 315 REDGPGVAL kidney, clear cell renalcell carcinoma, adrenal gland, adrenal cortical adenoma 316 REDPLPPGLkidney, clear cell renal cell carcinoma, adrenal gland, adrenal corticaladenoma 317 SLFGGSQGLRK kidney, clear cell renal cell carcinoma, adrenalgland, adrenal cortical adenoma 318 AEFQRLKQA intramuscular lipoma 319EVIDGVPGKW intramuscular lipoma 320 IPKAPGKII intramuscular lipoma 321SHNGSAIRY intramuscular lipoma 322 TEVTVVGDKL intramuscular lipoma 323YASVVVKRY intramuscular lipoma 324 ATDLALYIK stomach, adenocarcinoma,thyroid gland, papillary carcinoma 325 AYHNWRHAF stomach,adenocarcinoma, thyroid gland, papillary carcinoma 326 EPLNIKDAYstomach, adenocarcinoma, thyroid gland, papillary carcinoma 327KIAATIISF stomach, adenocarcinoma, thyroid gland, papillary carcinoma328 KIFLHIHGL stomach, adenocarcinoma, thyroid gland, papillarycarcinoma 329 LEVILKKI stomach, adenocarcinoma, thyroid gland, papillarycarcinoma 330 SEHPLAQLY stomach, adenocarcinoma, thyroid gland,papillary carcinoma 331 VPSAQTLKI stomach, adenocarcinoma, thyroidgland, papillary carcinoma 332 AEYRSYVA stomach, metastatic adrenalgland, adrenal cortical carcinoma 333 ALAPGRGTLY stomach, metastaticadrenal gland, adrenal cortical carcinoma 334 GPRGTQAAL stomach,metastatic adrenal gland, adrenal cortical carcinoma 335 IEDPGTLHIstomach, metastatic adrenal gland, adrenal cortical carcinoma 336IEDPGTLHIW stomach, metastatic adrenal gland, adrenal cortical carcinoma337 RPIPIAVKY stomach, metastatic adrenal gland, adrenal corticalcarcinoma 338 VEKLLTNW stomach, metastatic, pancreas, adenocarcinoma 339FLDPDIGGVAV kidney, clear cell renal cell carcinoma, pancreas,adenocarcinoma 340 HTAPPENKTW kidney, clear cell renal cell carcinoma,pancreas, adenocarcinoma 341 LLDTPVKTQY kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 342 NAVKDFTSF kidney, clear cellrenal cell carcinoma, pancreas, adenocarcinoma 343 SGLLQIKKL kidney,clear cell renal cell carcinoma, pancreas, adenocarcinoma 344 YHDKNIVLLkidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma 345SVDPKNYPK pancreas, adenocarcinoma, colon, adenocarcinoma 346 AVGLVLPAKliver, hepatocellular carcinoma, cancer, thyroid gland, papillarycarcinoma 347 AVGLVLPAKL liver, hepatocellular carcinoma, cancer,thyroid gland, papillary carcinoma 348 ALLEVLSQK stomach,adenocarcinoma, breast, carcinoma 349 HEKQDTLVA kidney, clear cell renalcell carcinoma, spleen, chronic myeloid leukemia 350 KELELQIGM kidney,clear cell renal cell carcinoma, spleen, chronic myeloid leukemia 351MYSDVWKQL kidney, clear cell renal cell carcinoma, spleen, chronicmyeloid leukemia 352 RELQDEKAEL kidney, clear cell renal cell carcinoma,spleen, chronic myeloid leukemia 353 RITDVLDQK kidney, clear cell renalcell carcinoma, spleen, chronic myeloid leukemia 354 EVIKITGLK stomach,adenocarcinoma 355 HHVDITKKL stomach, adenocarcinoma, kidney, carcinoma356 LPFNVKVSV stomach, adenocarcinoma, stomach, gastrointestinal stromaltumor (GIST) 357 TLPRVLEI stomach, adenocarcinoma, bone, giant celltumor of bone 358 TVDLPKSPK stomach, adenocarcinoma, thyroid gland,nodular hyperplasia 359 AEHGLLLTA stomach, metastatic, uterin cervix,adenocarcinoma 360 AQAGALLQV stomach, metastatic, uterin cervix,adenocarcinoma 361 DGGFVLKV stomach, metastatic, uterin cervix,adenocarcinoma 362 IVYPSGKVY stomach, metastatic, uterin cervix,adenocarcinoma 363 KLDNQVSKV colon or rectum, prostate, benign nodularhyperplasia 364 SENVKLFSA colon or rectum, prostate, benign nodularhyperplasia 365 VQKLQNII colon or rectum, prostate, benign nodularhyperplasia 366 FSTPHGLEV pancreas, adenocarcinoma, spleen, chronicmyeloid leukemia 367 KRFHQKSDM pancreas, adenocarcinoma, spleen, chronicmyeloid leukemia 368 KTFGHAVSL pancreas, adenocarcinoma, spleen, chronicmyeloid leukemia 369 SSNLITHSR pancreas, adenocarcinoma, spleen, 370GVIDGHIYAV chronic myeloid leukemia stomach, metastatic, leiomyosarcoma371 IEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 372NAPPSEVLL pancreas, adenocarcinoma, lung, adenocarcinoma 373SIEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 374AQSQHNQSL spleen, extramedullary hematopoiesis 375 AQSRTNPQV spleen,extramedullary hematopoiesis 376 KMHDKVFAY spleen, extramedullaryhematopoiesis 377 TAKAPLSTV spleen, extramedullary hematopoiesis 378IPTRTVAI liver, hepatocellular carcinoma, lipoma 379 NHDRKHAV liver,hepatocellular carcinoma, lipoma 380 NNHDRKHAV liver, hepatocellularcarcinoma, lipoma 381 TPGGTRIIY liver, hepatocellular carcinoma, breast,carcinoma 382 EHWPSPETF bone, non-ossifying fibroma 383 EIITNTLSF bone,non-ossifying fibroma 384 EVRGALMSAF bone, non-ossifying fibroma 385IPRPILVLL bone, non-ossifying fibroma 386 LPNKNRDEL bone, non-ossifyingfibroma 387 QRIPAGAVL bone, non-ossifying fibroma 388 AEGPAGGFMVVpancreas, adenocarcinoma, spleen, chronic myeloid leukemia 389 AYYRDAEAYpancreas, adenocarcinoma, spleen, chronic myeloid leukemia 390 QVNRPLTMRpancreas, adenocarcinoma, spleen, chronic myeloid leukemia 391 RHSPVFQVYpancreas, adenocarcinoma, spleen, chronic myeloid leukemia 392 SLPVPNSAYpancreas, adenocarcinoma, spleen, chronic myeloid leukemia 393TLGPPGTAHLY pancreas, adenocarcinoma, spleen, chronic myeloid leukemia394 IEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 395NAPPSEVLL pancreas, adenocarcinoma, lung, adenocarcinoma 396SIEPAKETTTNV pancreas, adenocarcinoma, lung, adenocarcinoma 397DLYSGLNQR lymph node, Hodgkin's disease 398 KAKAKPVTR lymph node,Hodgkin's disease 399 AVLDKAMKAK liver, hepatocellular carcinoma, liver,hepatic adenoma 400 LELSTPLKI liver, hepatocellular carcinoma, liver,hepatic adenoma 401 LPLNLDTKY liver, hepatocellular carcinoma, liver,hepatic adenoma 402 TVIYRIQAL liver, hepatocellular carcinoma, liver,hepatic adenoma 403 DAHIYLNHI stomach, adenocarcinoma, pancreas,microcystic adenoma 404 NHIEPLKIQL stomach, adenocarcinoma, pancreas,microcystic adenoma 405 AYRPAVHPR thyroid gland, nodular hyperplasia 406LRAPLEHEL thyroid gland, nodular hyperplasia 407 RLFMVLLLK thyroidgland, nodular hyperplasia 408 RSPDVLKDF thyroid gland, nodularhyperplasia 409 ETAPGVHKR stomach, metastatic, non-Hodgkin's lymphoma410 LYHGYIYTY stomach, metastatic, non-Hodgkin's lymphoma 415 VVFDSPRNRliver, hepatocellular carcinoma, pancreas, adenocarcinoma 416 YPLGRILIlung, non-small cell lung carcinoma, pancreas, adenocarcinoma 417KEFAEFVTS pancreas, adenocarcinoma, pancreas, adenocarcinoma 418VMLDVPIRL pancreas, adenocarcinoma, pancreas, adenocarcinoma 419VPMTPLRTV liver, hepatocellular carcinoma, cancer, rectum,adenocarcinoma 420 QIDYKTLVL stomach, metastatic, leiomyosarcoma 421VEDPTIVRI stomach, metastatic, leiomyosarcoma 422 IPYQDLPHL kidney,clear cell renal cell carcinoma, lipoma 423 DTPFLTGHGR stomach,adenocarcinoma, bone, non- ossifying fibroma 424 EFYRALYI stomach,adenocarcinoma, bone, non- ossifying fibroma 425 RYYPQILTNK stomach,adenocarcinoma, bone, non- ossifying fibroma 426 KAYERHVL intestines,malignant carcinoid tumor 427 LPSPEFHDY intestines, malignant carcinoidtumor 428 SLYAHPIEH intestines, malignant carcinoid tumor 429 LVREPGSQAkidney, clear cell renal cell carcinoma, lymph node, Hodgkin's disease430 RLAGPGSEKY kidney, clear cell renal cell carcinoma, lymph node,Hodgkin's disease 431 SPGAGRNSVL kidney, clear cell renal cellcarcinoma, lymph node, Hodgkin's disease 432 SVQSDQGYISR kidney, clearcell renal cell carcinoma, lymph node, Hodgkin's disease 433 GVRPPAPSLliver, hepatocellular carcinoma, kidney, carcinoma 434 IFSEKPVFV liver,hepatocellular carcinoma, kidney, carcinoma 435 KASNLLLGF liver,hepatocellular carcinoma, kidney, carcinoma 436 KRYIFADAY liver,hepatocellular carcinoma, kidney, carcinoma 437 RNLQLSLPR liver,hepatocellular carcinoma, kidney, carcinoma 438 EASEPVALR brain,glioblastoma, liver, hepatic adenoma 439 RPKVPDQSV brain, glioblastoma,liver, hepatic adenoma 440 VLYENALKL spleen, extramedullaryhematopoiesis 441 EVLDKSQTNY liver, hepatocellular carcinoma,endometrium, hyperplasia 442 MPSPIPAKY liver, hepatocellular carcinoma,endometrium, hyperplasia 443 YGIENFTSV liver, hepatocellular carcinoma,endometrium, hyperplasia 444 ARAAQVFFL colon or rectum, kidney, renalcell carcinoma 445 EHIVPNAEL colon or rectum, kidney, renal cellcarcinoma 446 EAFEFVKQR stomach, adenocarcinoma, breast, carcinoma 447NHFEGHYQY stomach, adenocarcinoma, breast, carcinoma 448 DAYPKNPHLstomach, adenocarcinoma, liver, hepatocellular carcinoma 449 DVNIKSTERstomach, adenocarcinoma, liver, hepatocellular carcinoma 450 HINSIKSVFstomach, adenocarcinoma, liver, hepatocellular carcinoma 451 YESEKVGVAstomach, adenocarcinoma, liver, hepatocellular carcinoma 452 ENAPTTVSRstomach, adenocarcinoma, adrenal gland, adrenal cortical adenoma 453RFPHLLAHTY stomach, adenocarcinoma, adrenal gland, adrenal corticaladenoma 454 TLDGSLHAV stomach, adenocarcinoma, adrenal gland, adrenalcortical adenoma 455 RTVLKNLSLLK liver, hepatocellular carcinoma,pancreas, microcystic adenoma 456 FEAKVQAI stomach, adenocarcinoma,metastatic adenocarcinoma of stomach 457 FFEAKVQAI stomach,adenocarcinoma, metastatic adenocarcinoma of stomach 458 KELQSTFKstomach, adenocarcinoma, metastatic adenocarcinoma of stomach 459NVSSRFEEEI stomach, adenocarcinoma, metastatic adenocarcinoma of stomach460 EVWNNLGTTK brain, cancer, lymph node, malignant melanoma 461MIFRSGSLI brain, cancer, lymph node, malignant melanoma 462 NHALPLPGFbrain, cancer, lymph node, malignant melanoma 463 ASVFGTMPLK kidney,polycystic kidney disease 464 REFPDRLVGY kidney, polycystic kidneydisease 465 SVFGTMPLK kidney, polycystic kidney disease 466 DEMRFVTQIlung, non-small cell lung carcinoma, testis, mixed germ cell tumor 467ETVHFATTQW lung, non-small cell lung carcinoma, testis, mixed germ celltumor 468 LPPPATQI lung, non-small cell lung carcinoma, testis, mixedgerm cell tumor 469 LARDLYAF liver, hepatocellular carcinoma,neuroblastoma 470 LPGIGLSTSL liver, hepatocellular carcinoma,neuroblastoma 471 MEVILPML liver, hepatocellular carcinoma,neuroblastoma 472 AILDYILAK stomach, metastatic, lung, neuroendocrinecarcinoma (non-small cell type) 473 KIASQLSKL stomach, metastatic, lung,neuroendocrine carcinoma (non-small cell type) 474 KVTSTTTVK stomach,metastatic, lung, neuroendocrine carcinoma (non-small cell type) 475YNTLLPYTF stomach, metastatic, lung, neuroendocrine carcinoma (non-smallcell type) 476 FLDPRPLTV pancreas, adenocarcinoma, myometrium, leiomyoma477 SAFADRPAF pancreas, adenocarcinoma, myometrium, leiomyoma 478AAVPVIISR lymph node, papillary carcinoma of thyroid 479 EEIGKVAAA lymphnode, papillary carcinoma of thyroid 480 FLKDLVASV lymph node, papillarycarcinoma of thyroid 481 VIISRALEL lymph node, papillary carcinoma ofthyroid 482 APRTTGTPRTSL kidney, oncocytoma 483 ESVGGSPQTK kidney,oncocytoma 484 IPKDKAIL kidney, oncocytoma 485 LPAYGRTTL kidney,oncocytoma 486 HQAAIVSKI stomach, adenocarcinoma, kidney, angiomyolipoma487 QAAIVSKI stomach, adenocarcinoma, kidney, angiomyolipoma 488RQKMPEDGL stomach, adenocarcinoma, kidney, angiomyolipoma 489 SVQKSSGVKstomach, adenocarcinoma, kidney, angiomyolipoma 490 DSIGSTVSSER stomach,adenocarcinoma 491 LPYNNKDRDAL stomach, adenocarcinoma 492 IYDEIQQEMcolon or rectum, colon, adenoma 493 AQAKGLIQV thymus, thymoma, benign494 EVSSEIYQW thymus, thymoma, benign 495 KWNPVPLSY thymus, thymoma,benign 496 NRLLAQQSL thymus, thymoma, benign 497 APRPVAVAV stomach,adenocarcinoma 498 FYRETVQVGR stomach, adenocarcinoma 499 LLAPRPVAVstomach, adenocarcinoma 500 GLAALVILK stomach, adenocarcinoma,neurofibroma 501 KIQEVFSSY stomach, adenocarcinoma, neurofibroma 502ASLDKFLSH spleen, chronic myeloid leukemia 503 ALYATKTLR colon orrectum, pancreas, microcystic adenoma 504 MEYVISRI colon or rectum,pancreas, microcystic adenoma 505 VPVGRQPII colon or rectum, pancreas,microcystic adenoma 506 KLLIGVIAAV stomach, metastatic, colon,adenocarcinoma 507 LPSLIKLD stomach, metastatic, colon, adenocarcinoma508 PSLIKLDL stomach, metastatic, colon, adenocarcinoma 509 ARNKELIGKstomach, adenocarcinoma 510 AVKSNAAAY stomach, adenocarcinoma 511EVIIPHSGW stomach, adenocarcinoma 512 SVKEQEAQF stomach, adenocarcinoma513 APRGLEPIAI liver, hepatocellular carcinoma, liver, focal nodularhyperplasia 514 GRFGGVITI liver, hepatocellular carcinoma, liver, focalnodular hyperplasia 518 AEHIESRTL kidney, clear cell renal cellcarcinoma, liver, focal nodular hyperplasia 519 DQYPYLKSV kidney, clearcell renal cell carcinoma, liver, focal nodular hyperplasia 520IARNLTQQL kidney, clear cell renal cell carcinoma, liver, focal nodularhyperplasia 521 IESRTLAIA kidney, clear cell renal cell carcinoma,liver, focal nodular hyperplasia 522 MTSALPIIQK kidney, clear cell renalcell carcinoma, liver, focal nodular hyperplasia 523 SLLTSSKGQLQKkidney, clear cell renal cell carcinoma, liver, focal nodularhyperplasia 524 TSALPIIQK kidney, clear cell renal cell carcinoma,liver, focal nodular hyperplasia 525 VRLGSLSTK kidney, clear cell renalcell carcinoma, liver, focal nodular hyperplasia 526 RINEFSISSFchondrosarcoma 527 DEKQQHIVY liver, hepatocellular carcinoma, synovialsarcoma 528 DEVYQVTVY liver, hepatocellular carcinoma, synovial sarcoma529 GEISEKAKL liver, hepatocellular carcinoma, synovial sarcoma 530YTMKEVLFY liver, hepatocellular carcinoma, synovial sarcoma 531SQLTTLSFY lung, non-small cell lung carcinoma, omentum, adenocarcinoma532 LEKQLIEL stomach, adenocarcinoma, rectum, adenocarcinoma 533ELTLGEFLK stomach, metastatic, ovary, Mullerian mixed tumor 534 LTLGEFLKstomach, metastatic, ovary, Mullerian mixed tumor 535 LTLGEFLKL stomach,metastatic, ovary, Mullerian mixed tumor 536 TLGEFLKL stomach,metastatic, ovary, Mullerian mixed tumor 537 ITARPVLW non-Hodgkin'slymphoma 538 KLMSPKLYVW non-Hodgkin's lymphoma 539 KVSAVTLAYnon-Hodgkin's lymphoma 540 VEGSGELFRW non-Hodgkin's lymphoma 541RPKSNIVL non-Hodgkin's lymphoma 542 RPKSNIVLL non-Hodgkin's lymphoma 543GEPLSYTRFSLARQ lung, non-small cell lung carcinoma, lung, adenocarcinoma544 GEPLSYTRFSLARQVD lung, non-small cell lung carcinoma, lung,adenocarcinoma 545 GEPLSYTRFSLARQVD lung, non-small cell lung carcinoma,G lung, adenocarcinoma 546 GGEPLSYTRFSLARQV lung, non-small cell lungcarcinoma, D lung, adenocarcinoma 547 GGEPLSYTRFSLARQV lung, non-smallcell lung carcinoma, DG lung, adenocarcinoma 548 NPGGYVAYSKAATVT lung,non-small cell lung carcinoma, G lung, adenocarcinoma 549NPGGYVAYSKAATVT lung, non-small cell lung carcinoma, GK lung,adenocarcinoma 550 NPGGYVAYSKAATVT lung, non-small cell lung carcinoma,GKL lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small cell lungcarcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung, non-small celllung carcinoma, lung, adenocarcinoma 553 NSVIIVDKNGRLVY lung, non-smallcell lung carcinoma, lung, adenocarcinoma 554 RVEYHFLSPYVSPK lung,non-small cell lung carcinoma, lung, adenocarcinoma 555 RVEYHFLSPYVSPKElung, non-small cell lung carcinoma, lung, adenocarcinoma 556RVEYHFLSPYVSPKES lung, non-small cell lung carcinoma, PF lung,adenocarcinoma 557 SPFRHVFWGSGSHTL lung, non-small cell lung carcinoma,lung, adenocarcinoma 558 SVIIVDKNGRLV lung, non-small cell lungcarcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung, non-small celllung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKE lung, non-smallcell lung carcinoma, lung, adenocarcinoma 561 LPSQAFEYILYNKG lung,non-small cell lung carcinoma, lung, adenocarcinoma 562 LPSQAFEYILYNKGIlung, non-small cell lung carcinoma, lung, adenocarcinoma 563LPSQAFEYILYNKGIM lung, non-small cell lung carcinoma, lung,adenocarcinoma 564 LPSQAFEYILYNKGIM lung, non-small cell lung carcinoma,G lung, adenocarcinoma 565 MNGYFLIERGKNM lung, non-small cell lungcarcinoma, lung, adenocarcinoma 566 NGYFLIERGKNm lung, non-small celllung carcinoma, lung, adenocarcinoma 567 PSQAFEYILYNKG lung, non-smallcell lung carcinoma, lung, adenocarcinoma 568 PSQAFEYILYNKGI lung,non-small cell lung carcinoma, lung, adenocarcinoma 569 PSQAFEYILYNKGIMlung, non-small cell lung carcinoma, lung, adenocarcinoma 570EGVQYSYSLFHLM stomach, metastatic, stomach, gastrointestinal stromaltumor (GIST) 571 EGVQYSYSLFHLML stomach, metastatic, stomach,gastrointestinal stromal tumor (GIST) 572 GVQYSYSLFHLM stomach,metastatic, stomach, gastrointestinal stromal tumor (GIST) 573GVQYSYSLFHLML stomach, metastatic, stomach, gastrointestinal stromaltumor (GIST) 574 SIISIHPKIQEHQPR stomach, metastatic, stomach,gastrointestinal stromal tumor (GIST) 575 SSIRTSTNSQVDK stomach,metastatic, stomach, gastrointestinal stromal tumor (GIST) 576VLVGYKAVYRIS stomach, metastatic, stomach, gastrointestinal stromaltumor (GIST) 577 YSSIRTSTNSQVDK stomach, metastatic, stomach,gastrointestinal stromal tumor (GIST) 578 GGGYGSGGGSGGYGS colon orrectum, thymus, thymoma, RRF malignant 579 GGSFGGRSSGSP colon or rectum,thymus, thymoma, malignant 580 KGGSFGGRSSGSP colon or rectum, thymus,thymoma, malignant 581 SGQQQSNYGPMKGGS colon or rectum, thymus, thymoma,FGGRSSGSPY malignant 582 SGSPYGGGYGSGGGS colon or rectum, thymus,thymoma, GGYGSRRF malignant 583 SPYGGGYGSGGGSGG colon or rectum, thymus,thymoma, YGSRRF malignant 584 YGGGYGSGGGSGGYG colon or rectum, thymus,thymoma, SRRF malignant 585 GNRINEFSISSF chondrosarcoma 586HGNQITSDKVGRKV chondrosarcoma 587 IPPVNTNLENLYLQ chondrosarcoma 588LQVLRLDGNEIKR chondrosarcoma 589 LQVLRLDGNEIKRS chondrosarcoma 590LQVLRLDGNEIKRSA chondrosarcoma 591 LRELHLDHNQISRVPN chondrosarcoma 592LYVRLSHNSLTNNG chondrosarcoma 593 VPSRMKYVYFQNNQ chondrosarcoma 594VPSRMKYVYFQNNQIT chondrosarcoma 595 VPSRMKYVYFQNNQIT chondrosarcoma S596 WIALHGNQITSD chondrosarcoma 597 WIALHGNQITSDK chondrosarcoma 598ADDNVSFRWEALGNT chondrosarcoma 599 ADDNVSFRWEALGNT colon or rectum L 600DADDNVSFRWEALGN colon or rectum TL 601 DDNVSFRWEALGNT colon or rectum602 DDNVSFRWEALGNTL colon or rectum 603 DNVSFRWEALGNT colon or rectum604 DNVSFRWEALGNTL colon or rectum 605 DNVSFRWEALGNTLS colon or rectum606 DTGSYRAQISTKTSAK colon or rectum 607 DTGSYRAQISTKTSAK colon orrectum L 608 DTITIYSTINHSK colon or rectum 609 EDTGSYRAQISTKTSA colon orrectum K 610 ENDTITIYSTINHSK colon or rectum 611 ENDTITIYSTINHSKES colonor rectum KPT 612 GSYRAQISTKTSAK colon or rectum 613 NDTITIYSTINH colonor rectum 614 NDTITIYSTINHS colon or rectum 615 NDTITIYSTINHSK colon orrectum 616 NVSFRWEALGNTL colon or rectum 617 SPTNNTVYASVTHSNR colon orrectum ET 618 TGSYRAQISTKTSAK colon or rectum 619 TPRENDTITIYSTINHScolon or rectum K 620 TPRENDTITIYSTINHS colon or rectum KESKPT 621VSFRWEALGNTL colon or rectum 622 APIHFTIEKLELNEK lipoma 623DAQFEVIKGQTIE lipoma 624 DAQFEVIKGQTIEVR lipoma 625 ESYFIPEVRIYDSGTlipoma 626 IPEVRIYDSGTY lipoma 627 KDKAIVAHNRHGNK lipoma 628KDKAIVAHNRHGNKA lipoma 629 NFVILEFPVEEQDR lipoma 630 SQPRISYDAQFEVIKlipoma 631 SQPRISYDAQFEVIKG lipoma 632 YDAQFEVIKGQTIE lipoma 633GNPAYRSFSNSLSQ colon or rectum, kidney, angiomyolipoma 634GPPGEAGYKAFSSLLA colon or rectum, kidney, angiomyolipoma 635GPPGEAGYKAFSSLLA colon or rectum, kidney, SS angiomyolipoma 636GPPGEAGYKAFSSLLA colon or rectum, kidney, SSA angiomyolipoma 637GPPGEAGYKAFSSLLA colon or rectum, kidney, SSAVSPE angiomyolipoma 638GPPGEAGYKAFSSLLA colon or rectum, kidney, SSAVSPEK angiomyolipoma 639GYKAFSSLLASSAVSP colon or rectum, kidney, angiomyolipoma 640GYKAFSSLLASSAVSP colon or rectum, kidney, E angiomyolipoma 641KAFSSLLASSAVSPE colon or rectum, kidney, angiomyolipoma 642NPAYRSFSNSLSQ colon or rectum, kidney, angiomyolipoma 643SRDDFQEGREGIVAR colon or rectum, kidney, angiomyolipoma 644SSSSFHPAPGNAQ colon or rectum, kidney, angiomyolipoma 645 VARLTESLFLDLcolon or rectum, kidney, angiomyolipoma 646 VARLTESLFLDLLG colon orrectum, kidney, angiomyolipoma 647 VIAGNPAYRSFSN colon or rectum,kidney, angiomyolipoma 648 VPQPEPETWEQILRRN colon or rectum, kidney, VLQangiomyolipoma 649 YKAFSSLLASSAVS colon or rectum, kidney,angiomyolipoma 650 YKAFSSLLASSAVSP colon or rectum, kidney,angiomyolipoma 651 YKAFSSLLASSAVSPE colon or rectum, kidney,angiomyolipoma, 652 GNQVFSYTANKEIRTD colon or rectum, urinary bladder, Dtransitional cell carcinoma 653 IEEIVLVDDASERD colon or rectum, urinarybladder, transitional cell carcinoma 654 IEEIVLVDDASERDF colon orrectum, urinary bladder, transitional cell carcinoma 655 LENIYPDSQIPRHcolon or rectum, urinary bladder, transitional cell carcinoma 656LENIYPDSQIPRHY colon or rectum, urinary bladder, transitional cellcarcinoma 657 NQVFSYTANKEIR colon or rectum, urinary bladder,transitional cell carcinoma 658 NQVFSYTANKEIRT colon or rectum, urinarybladder, transitional cell carcinoma 659 NQVFSYTANKEIRTDD colon orrectum, urinary bladder, transitional cell carcinoma 660 VHSVINRSPRHMIEEcolon or rectum, urinary bladder, transitional cell carcinoma 661EYVSLYHQPAAM non-Hodgkin's lymphoma 662 IKAEYKGRVTLKQYPR non-Hodgkin'slymphoma 663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma 664 LPYLFQmPAYASSSnon-Hodgkin's lymphoma 665 LPYLFQmPAYASSSK non-Hodgkin's lymphoma 666NFIKAEYKGRVT non-Hodgkin's lymphoma 667 TNFIKAEYKGRVT non-Hodgkin'slymphoma 668 TTNFIKAEYKGRVT non-Hodgkin's lymphoma 669 VTLNVHSEYEPSWEEQnon-Hodgkin's lymphoma P 670 YPRKNLFLVEVTQLTE non-Hodgkin's lymphoma SDS671 YPRKNLFLVEVTQLTE non-Hodgkin's lymphoma SDSG 672 ADLSSFKSQELN lymphnode, papillary carcinoma of thyroid 673 ADLSSFKSQELNER lymph node,papillary carcinoma of thyroid 674 ADLSSFKSQELNERN lymph node, papillarycarcinoma of thyroid 675 ADLSSFKSQELNERNE lymph node, papillarycarcinoma of thyroid 676 ADLSSFKSQELNERNE lymph node, papillarycarcinoma of A thyroid 677 AEQQRLKSQDLELSW lymph node, papillarycarcinoma of NLNG thyroid, metastatic 678 EQQRLKSQDLELSWN lymph node,papillary carcinoma of thyroid 679 ISQELEELRAEQQR lymph node, papillarycarcinoma of thyroid 680 ISQELEELRAEQQRLK lymph node, papillarycarcinoma of thyroid 681 KGTKQWVHARYA lymph node, papillary carcinoma ofthyroid 682 QADLSSFKSQELNER lymph node, papillary carcinoma of thyroid,metastatic 683 SWNLNGLQADLSSFK lymph node, papillary carcinoma ofthyroid 684 TGSWIGLRNLDLKG lymph node, papillary carcinoma of thyroid685 FGNYNNQSSNFGPMK pancreas, adenocarcinoma, thymus, GGNFGGRS thymoma,malignant 686 FGPMKGGNFGGRSSGP pancreas, adenocarcinoma, thymus, YGGGGQYthymoma, malignant 687 GPMKGGNFGGRSSGP pancreas, adenocarcinoma, thymus,thymoma, malignant 688 GPYGGGGQYFAKP pancreas, adenocarcinoma, thymus,thymoma, malignant 689 KGGNFGGRSSGP pancreas, adenocarcinoma, thymus,thymoma, malignant 690 NDFGNYNNQSSNFGP pancreas, adenocarcinoma, thymus,thymoma, malignant 691 SGPYGGGGQYFAKP pancreas, adenocarcinoma, thymus,thymoma, malignant 692 DAGSYKAQINQRNFE lung, non-small cell lungcarcinoma, lymph node, non-Hodgkin's lymphoma 693 DAGSYKAQINQRNFEV lung,non-small cell lung carcinoma, T lymph node, non-Hodgkin's lymphoma 694DGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 695GELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 696NPSDGELIRTQPQRLP pancreas, adenocarcinoma, intramuscular lipoma 697NPSDGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 698NPSDGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular L lipoma 699ASNDMYHSRALQVVR colon or rectum, bone, giant cell tumor of bone 700ASNDMYHSRALQVVR colon or rectum, bone, giant cell tumor A of bone 701EGVRRALDFAVGEYN colon or rectum, bone, giant cell tumor of bone 702EGVRRALDFAVGEYN colon or rectum, bone, giant cell tumor K of bone 703SNDMYHSRALQVVR colon or rectum, bone, giant cell tumor of bone 704VGEYNKASNDMYH colon or rectum, bone, giant cell tumor of bone 705VRARKQIVAGVNY colon or rectum, bone, giant cell tumor of bone 706VRRALDFAVGEYNKA colon or rectum, bone, giant cell tumor SND of bone 707VVRARKQIVAGVN colon or rectum, bone, giant cell tumor of bone 708VVRARKQIVAGVNY colon or rectum, bone, giant cell tumor of bone 709APLEGARFALVRED liver, hepatocellular carcinoma 710 APVELILSDETLPAPEliver, hepatocellular carcinoma 711 ELILSDETLPAPE liver, hepatocellularcarcinoma 712 LAPLEGARFALVRE liver, hepatocellular carcinoma 713LAPLEGARFALVRED liver, hepatocellular carcinoma 714 RGEKELLVPRSSTSPDliver, hepatocellular carcinoma 715 ASKTFTTQETITNAET kidney, clear cellrenal cell carcinoma, kidney, angiomyolipoma 716 DQHFRTTPLEKNAPV kidney,clear cell renal cell carcinoma, kidney, angiomyolipoma 717NTPILVDGKDVMPE kidney, clear cell renal cell carcinoma, kidney,angiomyolipoma 718 NTPILVDGKDVMPEV kidney, clear cell renal cellcarcinoma, kidney, angiomyolipoma 719 NTPILVDGKDVMPEVN kidney, clearcell renal cell carcinoma, kidney, angiomyolipoma 720 SNTPILVDGKDVMPEkidney, clear cell renal cell carcinoma, kidney, angiomyolipoma 721SNTPILVDGKDVMPEV kidney, clear cell renal cell carcinoma, N kidney,angiomyolipoma 722 TPILVDGKDVMP kidney, clear cell renal cell carcinoma,kidney, angiomyolipoma 723 TPILVDGKDVMPE kidney, clear cell renal cellcarcinoma, kidney, angiomyolipoma 724 TPILVDGKDVMPEV kidney, clear cellrenal cell carcinoma, kidney, angiomyolipoma 725 TPILVDGKDVMPEVN kidney,clear cell renal cell carcinoma, kidney, angiomyolipoma 726GPLKFLHQDIDSGQG kidney, renal cell carcinoma 727 GPLKFLHQDIDSGQGIkidney, renal cell carcinoma R 728 LGDIYFKLFRASG kidney, renal cellcarcinoma 729 TGHLFDLSSLSGRAG kidney, renal cell carcinoma 730VPSPVDCQVTDLAGNE kidney, renal cell carcinoma 731 DGLNSLTYQVLDVQRkidney, clear cell renal cell carcinoma, YPL endometrium,adenocarcinoma, endometrioid type 732 HPVLQRQQLDYGIY kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 733LNSLTYQVLDVQR kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 734 LNSLTYQVLDVQRYP kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 735LNSLTYQVLDVQRYPL kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 736 LPQLVGVSTPLQG kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 737LPQLVGVSTPLQGG kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 738 LPQLVGVSTPLQGGS kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 739RLPQLVGVSTPLQGGS kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 740 SPHKVAIIIPFRNR kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 741SPHKVAIIIPFRNRQE kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 742 SPHKVAIIIPFRNRQEH kidney, clearcell renal cell carcinoma, endometrium, adenocarcinoma, endometrioidtype 743 AIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 744ARNFERNKAIKVI non-Hodgkin's lymphoma, peripheral T cell type 745ARNFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 746NFERNKAIKVII non-Hodgkin's lymphoma, peripheral T cell type 747NFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 748VAIVQAVSAHRH non-Hodgkin's lymphoma, peripheral T cell type 749VAIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 750VAIVQAVSAHRHRA non-Hodgkin's lymphoma, peripheral T cell type 751VAIVQAVSAHRHRAR non-Hodgkin's lymphoma, peripheral T cell type 752EEVITLIRSNQQLE lung, non-small cell lung carcinoma, pancreas,adenocarcinoma 753 EEVITLIRSNQQLEN lung, non-small cell lung carcinoma,pancreas, adenocarcinoma 754 IPADTFAALKNPNAML lung, non-small cell lungcarcinoma, pancreas, adenocarcinoma 755 LKQLLSDKQQKRQSG lung, non-smallcell lung carcinoma, pancreas, adenocarcinoma 756 LKQLLSDKQQKRQSG lung,non-small cell lung carcinoma, Q pancreas, adenocarcinoma 757TPSYVAFTDTER pancreas, adenocarcinoma, rectum, adenocarcinoma 758TPSYVAFTDTERL pancreas, adenocarcinoma, rectum, adenocarcinoma 759EGLYSRTLAGSIT liver, hepatocellular carcinoma, cancer, thyroid gland,nodular hyperplasia 760 EGLYSRTLAGSITTPP liver, hepatocellularcarcinoma, cancer, thyroid gland, nodular hyperplasia 761 EKWYIPDPTGKFNliver, hepatocellular carcinoma, cancer, thyroid gland, nodularhyperplasia 762 GAIAAINSIQHNTR liver, hepatocellular carcinoma, cancer,thyroid gland, nodular hyperplasia 763 LPILVPSAKKAI liver,hepatocellular carcinoma, cancer, thyroid gland, nodular hyperplasia 764LPILVPSAKKAIY liver, hepatocellular carcinoma, cancer, thyroid gland,nodular hyperplasia 765 LPILVPSAKKAIYM liver, hepatocellular carcinoma,cancer, thyroid gland, nodular hyperplasia 766 LPILVPSAKKAIYMD liver,hepatocellular carcinoma, cancer, thyroid gland, nodular hyperplasia 767LPILVPSAKKAIYMDD liver, hepatocellular carcinoma, cancer, thyroid gland,nodular hyperplasia 768 VEEGLYSRTLAGSIT liver, hepatocellular carcinoma,cancer, thyroid gland, nodular hyperplasia 769 WEKWYIPDPTGKFN liver,hepatocellular carcinoma, cancer, thyroid gland, nodular hyperplasia 770YKIVNFDPKLLE liver, hepatocellular carcinoma, cancer, thyroid gland,nodular hyperplasia 771 YKIVNFDPKLLEG liver, hepatocellular carcinoma,cancer, thyroid gland, nodular hyperplasia 772 YKIVNFDPKLLEGKV liver,hepatocellular carcinoma, cancer, thyroid gland, nodular hyperplasia 773LPEFYKTVSPAL colon or rectum, endometrium, adenocarcinoma, endometrioidtype 774 VGQFIQDVKNSRST colon or rectum, endometrium, adenocarcinoma,endometrioid type 775 VGQFIQDVKNSRSTD colon or rectum, endometrium,adenocarcinoma, endometrioid type 776 VVGQFIQDVKNSRS colon or rectum,endometrium, adenocarcinoma, endometrioid type 777 VVGQFIQDVKNSRST colonor rectum, endometrium, adenocarcinoma, endometrioid type 778VVGQFIQDVKNSRSTD colon or rectum, endometrium, adenocarcinoma,endometrioid type 779 VVGQFIQDVKNSRSTD colon or rectum, endometrium, Sadenocarcinoma, endometrioid type 780 DNGHLYREDQTSPAPG pancreas,adenocarcinoma, kidney, angiomyolipoma 781 DNGHLYREDQTSPAPG pancreas,adenocarcinoma, kidney, LR angiomyolipoma 782 EVQVFAPANALPARSE pancreas,adenocarcinoma, kidney, angiomyolipoma 783 GHLYREDQTSPAPG pancreas,adenocarcinoma, kidney, angiomyolipoma 784 LPARSEAAAVQPVIG pancreas,adenocarcinoma, kidney, angiomyolipoma 785 NGHLYREDQTSPAPG pancreas,adenocarcinoma, kidney, angiomyolipoma 786 NGHLYREDQTSPAPGL pancreas,adenocarcinoma, kidney, angiomyolipoma 787 NGHLYREDQTSPAPGL pancreas,adenocarcinoma, kidney, R angiomyolipoma 788 VFAPANALPARSEAA pancreas,adenocarcinoma, kidney, angiomyolipoma 789 VQVFAPANALPARSE pancreas,adenocarcinoma, kidney, angiomyolipoma 790 AIVVSDRDGVPVIK stomach,adenocarcinoma, parathyroid gland, adenoma 791 GLHAIVVSDRDGVPV stomach,adenocarcinoma, parathyroid gland, adenoma 792 GLHAIVVSDRDGVPVI stomach,adenocarcinoma, parathyroid K gland, adenoma 793 HAIVVSDRDGVPV stomach,adenocarcinoma, parathyroid gland, adenoma 794 KLPSVEGLHAIVVSDR stomach,adenocarcinoma, parathyroid DG gland, adenoma 795 LHAIVVSDRDGVPVstomach, adenocarcinoma, parathyroid gland, adenoma 796 LHAIVVSDRDGVPVIstomach, adenocarcinoma, parathyroid gland, adenoma 797 LHAIVVSDRDGVPVIKstomach, adenocarcinoma, parathyroid gland, adenoma 798 LPSVEGLHAIVVSDRstomach, adenocarcinoma, parathyroid gland, adenoma 799 VPVIKVANDNAPEstomach, adenocarcinoma, parathyroid gland, adenoma 800 YNTYQVVQFNRLPstomach, adenocarcinoma, parathyroid gland, adenoma 801 YNTYQVVQFNRLPLstomach, adenocarcinoma, parathyroid gland, adenoma 802 YNTYQVVQFNRLPLVstomach, adenocarcinoma, parathyroid gland, adenoma 803 YNTYQVVQFNRLPLVstomach, adenocarcinoma, parathyroid V gland, adenoma 804 YYNTYQVVQFNRLPstomach, adenocarcinoma, parathyroid gland, adenoma 805 YYNTYQVVQFNRLPLstomach, adenocarcinoma, parathyroid gland, adenoma 806 YYNTYQVVQFNRLPLstomach, adenocarcinoma, parathyroid V gland, adenoma 807 DKIYFmAGSSRKEliver, hepatocellular carcinoma, thyroid gland, nodular hyperplasia 808DVGTDEEEETAKESTA liver, hepatocellular carcinoma, thyroid EKDE gland,nodular hyperplasia 809 EVTFKSILFVPTSAP liver, hepatocellular carcinoma,thyroid gland, nodular hyperplasia 810 KSEKFAFQAEVNR liver,hepatocellular carcinoma, thyroid gland, nodular hyperplasia 811LPEFDGKRFQNVAK liver, hepatocellular carcinoma, thyroid gland, nodularhyperplasia 812 DGSYRIFSKGASE colon or rectum, liposarcoma 813GSYRIFSKGASE colon or rectum, liposarcoma 814 SDGSYRIFSKGASE colon orrectum, liposarcoma 815 SVKKMMKDNNLVRH colon or rectum, liver,hepatocellular carcinoma 816 VKKMMKDNNLVRH colon or rectum, liver,hepatocellular carcinoma 817 NNmRIFGEAAEKN stomach, adenocarcinoma,thyroid gland, papillary carcinoma 818 VDKVLERDQKLSE lung, non-smallcell lung carcinoma, lymph node, papillary carcinoma of thyroid 819VDKVLERDQKLSELD lung, non-small cell lung carcinoma, lymph node,papillary carcinoma of thyroid 820 VDKVLERDQKLSELD lung, non-small celllung carcinoma, D lymph node, papillary carcinoma of thyroid 821VDKVLERDQKLSELD stomach, adenocarcinoma, lymph node, DR papillarycarcinoma of thyroid 822 VLERDQKLSELDDR lung, non-small cell lungcarcinoma, lymph node, papillary carcinoma of thyroid 823ATRSIQVDGKTIKAQ stomach, adenocarcinoma, kidney, angiomyolipoma 824ATRSIQVDGKTIKAQI stomach, adenocarcinoma, kidney, angiomyolipoma 825IGVEFATRSIQVDGK stomach, adenocarcinoma, kidney, angiomyolipoma 826RSIQVDGKTIKA stomach, adenocarcinoma, kidney, angiomyolipoma 827RSIQVDGKTIKAQ stomach, adenocarcinoma, kidney, angiomyolipoma 828RSIQVDGKTIKAQI stomach, adenocarcinoma, kidney, angiomyolipoma 829TRSIQVDGKTIKAQ stomach, adenocarcinoma, kidney, angiomyolipoma 830DIMRVNVDKVLERDQ stomach, adenocarcinoma, medullary K carcinoma ofthyroid origin 831 DIMRVNVDKVLERDQ stomach, adenocarcinoma, medullary KLcarcinoma of thyroid origin 832 IMRVNVDKVLERDQK lung, non-small celllung carcinoma, lymph node, Hodgkin's disease 833 VDKVLERDQKLSE lung,non-small cell lung carcinoma, lymph node, papillary carcinoma ofthyroid 834 VDKVLERDQKLSELD lung, non-small cell lung carcinoma, lymphnode, papillary carcinoma of thyroid 835 VDKVLERDQKLSELD lung, non-smallcell lung carcinoma, D lymph node, papillary carcinoma of thyroid 836VDKVLERDQKLSELD stomach, adenocarcinoma, lymph node, DR papillarycarcinoma of thyroid 837 VLERDQKLSELDDR lung, non-small cell lungcarcinoma, lymph node, papillary carcinoma of thyroid 838ATRSIQVDGKTIKAQ stomach, adenocarcinoma 839 ATRSIQVDGKTIKAQI stomach,adenocarcinoma, kidney, angiomyolipoma 840 IGVEFATRSIQVDGK stomach,adenocarcinoma, kidney, angiomyolipoma 841 RSIQVDGKTIKA stomach,adenocarcinoma, kidney, angiomyolipoma 842 RSIQVDGKTIKAQ stomach,adenocarcinoma, kidney, angiomyolipoma 843 RSIQVDGKTIKAQI stomach,adenocarcinoma, kidney, angiomyolipoma 844 TRSIQVDGKTIKAQ stomach,adenocarcinoma, kidney, angiomyolipoma 845 GIRVAPVPLYNS lung, non-smallcell lung carcinoma, liver, hepatocellular carcinoma 846 GIRVAPVPLYNSFHlung, non-small cell lung carcinoma, liver, hepatocellular carcinoma 847NPNGIRVAPVPLYNSF lung, non-small cell lung carcinoma, H liver,hepatocellular carcinoma 848 DDPAIDVCKKLLGKYP kidney, clear cell renalcell carcinoma, N pancreas, adenocarcinoma 849 DKQPYSKLPGVSLLKP kidney,clear cell renal cell carcinoma, pancreas, adenocarcinoma 850DKQPYSKLPGVSLLKP kidney, clear cell renal cell carcinoma, L pancreas,adenocarcinoma 851 HPRYYISANVTGFK kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 852 SHPRYYISANVTG kidney, clear cellrenal cell carcinoma, pancreas, adenocarcinoma 853 SHPRYYISANVTGFKkidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma 854TSHPRYYISANVTG kidney, clear cell renal cell carcinoma, pancreas,adenocarcinoma 855 TSHPRYYISANVTGFK kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 856 ADIFVDPVLHTA kidney, renal cellcarcinoma 857 ADIFVDPVLHTACA kidney, renal cell carcinoma 858DPGADYRIDRALNEA kidney, renal cell carcinoma 859 IAQDYKVSYSLA kidney,renal cell carcinoma 860 IAQDYKVSYSLAK kidney, renal cell carcinoma 861ISRDWKLDPVLYRK kidney, renal cell carcinoma 862 LIAQDYKVSYSLA kidney,renal cell carcinoma 863 RQKLIAQDYKVSYS kidney, renal cell carcinoma 864RQKLIAQDYKVSYSL kidney, renal cell carcinoma 865 RQKLIAQDYKVSYSLAkidney, renal cell carcinoma 866 RQKLIAQDYKVSYSLA kidney, renal cellcarcinoma K 867 SALDYRLDPQLQLH kidney, renal cell carcinoma 868SKADIFVDPVLHTA kidney, renal cell carcinoma 869 SPSKNYILSVISGSI kidney,renal cell carcinoma 870 ETTQLTADSHPSYHTD stomach, metastatic, skin,squamous cell G carcinoma 871 SGESLYHVLGLDKNAT stomach, metastatic,skin, squamous cell SDD carcinoma 872 TTQLTADSHPSYHT stomach,metastatic, skin, squamous cell carcinoma 873 TTQLTADSHPSYHTD stomach,metastatic, skin, squamous cell carcinoma 874 TTQLTADSHPSYHTDG stomach,metastatic, skin, squamous cell carcinoma 875 SVEEFLSEKLERI pancreas,adenocarcinoma, liver, hepatic adenoma 876 VEEFLSEKLERI pancreas,adenocarcinoma, liver, hepatic adenoma 877 DLSSSILAQSRERVA pancreas,adenocarcinoma, bone, giant cell tumor of bone 878 EKGVRTLTAAAVSGApancreas, adenocarcinoma, bone, giant Q cell tumor of bone 879EKGVRTLTAAAVSGA pancreas, adenocarcinoma, bone, giant QP cell tumor ofbone 880 EKGVRTLTAAAVSGA pancreas, adenocarcinoma, bone, giant QPI celltumor of bone 881 KGVRTLTAAAVSGA pancreas, adenocarcinoma, bone, giantcell tumor of bone 882 KGVRTLTAAAVSGAQ pancreas, adenocarcinoma, bone,giant cell tumor of bone 883 VGPFAPGITEKAPEEK pancreas, adenocarcinoma,bone, giant K cell tumor of bone 884 DPPLIALDKDAPLR brain, glioblastoma,parotid gland, pleomorphic adenoma 885 EIITPDVPFTVDKDG brain,glioblastoma, parotid gland, pleomorphic adenoma 886 IITPDVPFTVDKDGbrain, glioblastoma, parotid gland, pleomorphic adenoma 887PPLIALDKDAPLR brain, glioblastoma, parotid gland, pleomorphic adenoma888 TNVKKSHKATVHIQ brain, glioblastoma, parotid gland, pleomorphicadenoma 889 DDNIKTYSDHPE kidney, clear cell renal cell carcinoma, liver,hepatocellular carcinoma 890 DDNIKTYSDHPEK kidney, clear cell renal cellcarcinoma, liver, hepatocellular carcinoma 891 DSAVFFEQGTTRIG kidney,clear cell renal cell carcinoma, liver, hepatocellular carcinoma 892GDKVYVHLKNLASRP kidney, clear cell renal cell carcinoma, Y liver,hepatocellular carcinoma 893 GDKVYVHLKNLASRP kidney, clear cell renalcell carcinoma, YT liver, hepatocellular carcinoma 894 VHLKNLASRPYTkidney, clear cell renal cell carcinoma, liver, hepatocellular carcinoma895 VYVHLKNLASRPY kidney, clear cell renal cell carcinoma, liver,hepatocellular carcinoma 896 VYVHLKNLASRPYT kidney, clear cell renalcell carcinoma, liver, hepatocellular carcinoma 897 VYVHLKNLASRPYTFHkidney, clear cell renal cell carcinoma, liver, hepatocellular carcinoma898 YVHLKNLASRPY kidney, clear cell renal cell carcinoma, liver,hepatocellular carcinoma 899 YVHLKNLASRPYT kidney, clear cell renal cellcarcinoma, liver, hepatocellular carcinoma 900 YVHLKNLASRPYTFH kidney,clear cell renal cell carcinoma, liver, hepatocellular carcinoma 901SNLIKLAQKVPTAD liver, hepatocellular carcinom 902 YDTRTSALSAKS liver,hepatocellular carcinoma 903 ALMTDPKLITWSPV bone, non-ossifying fibroma904 NDVAWNFEKFLVGPD bone, non-ossifying fibroma G 905 QSVYAFSARPLAGbone, non-ossifying fibroma 906 QSVYAFSARPLAGGEP bone, non-ossifyingfibroma V 907 WNFEKFLVGPDG colon or rectum, bone, non-ossifying fibroma908 DVGMFVALTKLGQPD stomach, adenocarcinoma, uterin cervix, squamouscell carcinoma 909 VGMFVALTKLGQPD stomach, adenocarcinoma, uterincervix, squamous cell carcinoma 910 AGVFHVEKNGRY stomach,adenocarcinoma, colon, adenocarcinoma 911 FAGVFHVEKNGRYS stomach,adenocarcinoma, colon, adenocarcinoma 912 GPITITIVNRDGTR stomach,adenocarcinoma, colon, adenocarcinoma 913 NGRYSISRTEAADL stomach,adenocarcinoma, colon, adenocarcinoma 914 RKSRQGSLAMEELK rectum,adenocarcinoma 915 RRKSRQGSLAMEELK rectum, adenocarcinoma 916EEFKKLTSIKIQNDK brain, glioblastoma, small Intestine, gastrointestinalstromal tumor (GIST) 917 INRRMADDNKLFR brain, glioblastoma, smallIntestine, gastrointestinal stromal tumor (GIST) 918 TATIVMVTNLKERKEbrain, glioblastoma, small Intestine, gastrointestinal stromal tumor(GIST) 919 ELFYKGIRPAINVG liver, hepatocellular carcinoma, kidney,oncocytoma 920 GQKRSTVAQLVKR liver, hepatocellular carcinoma, kidney,oncocytoma 921 SDLDAATQQLLSRGV liver, hepatocellular carcinoma, kidney,oncocytoma 922 FDFSQNTRVPRLPE kidney, clear cell renal cell carcinoma,non-Hodgkin's lymphoma 923 GDAPAILFDKEF kidney, clear cell renal cellcarcinoma, non-Hodgkin's lymphoma 924 VTHEIDRYTAIAY kidney, clear cellrenal cell carcinoma, non-Hodgkin's lymphoma 929 AAKYQLDPTASISA kidney,oncocytoma 930 IAAKYQLDPTASISA kidney, oncocytoma 931 IAAKYQLDPTASISAKkidney, oncocytoma 932 AGLGRAYALAFAERG liver, hepatocellular carcinoma,hepatic adenoma 933 DAFGRIDVVVNNAG liver, hepatocellular carcinoma,hepatic adenoma 934 GLGRAYALAFAER liver, hepatocellular carcinoma,hepatic adenoma 935 GLGRAYALAFAERG liver, hepatocellular carcinoma,hepatic adenoma 936 AKFALNGEEFMNFDL liver, hepatocellular carcinoma,liposarcoma 937 AKFALNGEEFMNFDL liver, hepatocellular carcinoma, Kliposarcoma 938 ALNGEEFMNFDLK liver, hepatocellular carcinoma,liposarcoma 939 KFALNGEEFMNFDL liver, hepatocellular carcinoma,liposarcoma 940 SDGSFHASSSLTVK liver, hepatocellular carcinoma,liposarcoma 941 EERNLLSVAYKNVVG colon or rectum, esophagus, ARadenocarcinoma 942 ERNLLSVAYKNVVGA colon or rectum, esophagus, Radenocarcinoma 943 IAELDTLSEESYKD colon or rectum, Vulva, squamous cellcarcinoma 944 IAELDTLSEESYKDS colon or rectum, Vulva, squamous cellcarcinoma 945 ADSYLDEGFLLDKKIG lung, non-small cell lung carcinoma,ovary, Mullerian mixed tumor 946 DSYLDEGFLLDKK lung, non-small cell lungcarcinoma, ovary, Mullerian mixed tumor 947 DSYLDEGFLLDKKIG lung,non-small cell lung carcinoma, ovary, Mullerian mixed tumor 948VDNIIKAAPRKRVPD lung, non-small cell lung carcinoma, ovary, Mullerianmixed tumor 949 SPPQFRVNGAISN colon or rectum, ovary, granulosa celltumor 950 SPPQFRVNGAISNFE colon or rectum, ovary, granulosa cell tumor951 SPPQFRVNGAISNFEE colon or rectum, ovary, granulosa cell tumor 952SPPQFRVNGAISNFEEF colon or rectum, ovary, granulosa cell tumor 953VGKMFVDVYFQEDKK colon or rectum, ovary, granulosa cell tumor 954VGKMFVDVYFQEDKK colon or rectum, ovary, granulosa cell E tumor 955DPKRTIAQDYGVLKA lung, non-small cell lung carcinoma, DE thyroid gland,nodular hyperplasia 956 DPKRTIAQDYGVLKA lung, non-small cell lungcarcinoma, DEG thyroid gland, nodular hyperplasia 957 PKRTIAQDYGVLKADElung, non-small cell lung carcinoma, G thyroid gland, nodularhyperplasia 958 GLFIIDDKGILRQ lung, non-small cell lung carcinoma,thyroid gland, nodular hyperplasia 959 GLFIIDDKGILRQIT lung, non-smallcell lung carcinoma, thyroid gland, nodular hyperplasia 960RGLFIIDDKGILR lung, non-small cell lung carcinoma, thyroid gland,nodular hyperplasia 961 RGLFIIDDKGILRQ lung, non-small cell lungcarcinoma, thyroid gland, nodular hyperplasia 962 RGLFIIDDKGILRQIT lung,non-small cell lung carcinoma, thyroid gland, nodular hyperplasia 963GNTVIHLDQALARMR brain, glioblastoma, lung, small cell carcinoma 964NTVIHLDQALARMR brain, glioblastoma, lung, small cell carcinoma 965NTVIHLDQALARMRE brain, glioblastoma, lung, small cell carcinoma 966ENNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 967NNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 968SPTVQVFSASGKPV stomach, adenocarcinoma, kidney, oncocytoma 969SSPTVQVFSASGKPVE stomach, adenocarcinoma, kidney, oncocytoma 970AEPNYHSLPSARTDEQ thyroid gland, follicular adenoma 971 SSILAKTASNIIDVSthyroid gland, follicular adenoma 973 ADDLEGEAFLPL stomach,adenocarcinoma, spleen, chronic myeloid leukemia 974 ADDLEGEAFLPLRstomach, adenocarcinoma, spleen, chronic myeloid leukemia 975ADDLEGEAFLPLRE stomach, adenocarcinoma, spleen, chronic myeloid leukemia976 GADDLEGEAFLPLR stomach, adenocarcinoma, spleen, chronic myeloidleukemia 977 AGREINLVDAHLKSE lymph node, Hodgkin's disease 978AGREINLVDAHLKSEQ lymph node, Hodgkin's disease T 979 GREINLVDAHLKSElymph node, Hodgkin's disease 980 KPGIVYASLNHSVIG lymph node, Hodgkin'sdisease 981 NKPGIVYASLNHSVIG lymph node, Hodgkin's disease 982TTLYVTDVKSASERPS lymph node, Hodgkin's disease 983 APSTYAHLSPAKTPPPstomach, adenocarcinoma, pancreas, adenocarcinoma 984 APSTYAHLSPAKTPPPPstomach, adenocarcinoma, pancreas, adenocarcinoma 985 APSTYAHLSPAKTPPPPstomach, adenocarcinoma, pancreas, A adenocarcinoma 986 RDDLYDQDDSRDFPRstomach, adenocarcinoma, pancreas, adenocarcinoma 987 TRPYHSLPSEAVFAadrenal gland, adrenal cortical adenoma 988 TRPYHSLPSEAVFAN adrenalgland, adrenal cortical adenoma 989 VAVFTFHNHGRT adrenal gland, adrenalcortical adenoma 990 VAVFTFHNHGRTA adrenal gland, adrenal corticaladenoma 991 VAVFTFHNHGRTANL adrenal gland, adrenal cortical adenoma 992EDDYIKSWEDNQQGD brain, glioblastoma, pleura, malignant E mesothelioma993 ELERIQIQEAAKKKPG brain, glioblastoma, pleura, malignant mesothelioma994 ERIQIQEAAKKKP brain, glioblastoma, pleura, malignant mesothelioma995 ERIQIQEAAKKKPG brain, glioblastoma, pleura, malignant mesothelioma996 ERIQIQEAAKKKPGI brain, glioblastoma, pleura, malignant mesothelioma997 LERIQIQEAAKKKPG brain, glioblastoma, pleura, malignant mesothelioma998 LSSISQYSGKIK brain, glioblastoma, pleura, malignant mesothelioma 999SPAKDSLSFEDF rectum, adenocarcinoma 1000 SPAKDSLSFEDFLDL rectum,adenocarcinoma 1001 INSRFPIPSATDPD brain, glioblastoma, brain,oligodendroglioma 1002 VQHYELLNGQSVFG brain, glioblastoma, brain,oligodendroglioma 1003 DNQYAVLENQKSSH colon or rectum, pleura, malignantmesothelioma 1004 GPPEIYSDTQFPS colon or rectum, pleura, malignantmesothelioma 1005 GPPEIYSDTQFPSLQ colon or rectum, pleura, malignantmesothelioma 1006 TPQGPPEIYSDTQFPS colon or rectum, pleura, malignantmesothelioma 1007 TPQGPPEIYSDTQFPSL colon or rectum, pleura, malignant Qmesothelioma 1008 TPQGPPEIYSDTQFPSL colon or rectum, pleura, malignantQST mesothelioma 1009 ANLQRAYSLAKEQR kidney, clear cell renal cellcarcinoma, adrenal gland, adrenal cortical carcinoma 1010 NLQRAYSLAKEQRkidney, clear cell renal cell carcinoma, adrenal gland, adrenal corticalcarcinoma 1011 TPSGITYDRKDIEEH kidney, clear cell renal cell carcinoma,adrenal gland, adrenal cortical carcinoma 1012 VSTLNSEDFVLVSR brain,glioblastoma, kidney, angiomyolipoma 1013 VSTLNSEDFVLVSRQ brain,glioblastoma, kidney, angiomyolipoma 1014 VSTLNSEDFVLVSRQG brain,glioblastoma, kidney, angiomyolipoma 1015 GSSFFGELFNQNPE brain,glioblastoma, thyroid gland, papillary carcinoma 1016 SGSSFFGELFNQNPEbrain, glioblastoma, thyroid gland, papillary carcinoma

Thus, another aspect of the present invention relates to the use of thepeptides according to the present invention for the—preferablycombined—treatment of a proliferative disease selected from the group ofadrenal cortical adenoma; non-ossifying fibroma; brain cancer and aproliferative disease selected from kidney oncocytoma, kidney Wilm'stumor, lymph node malignant melanoma, and omentum leiomyosarcoma;glioblastoma and a proliferative disease selected fromoligodendroglioma, kidney angiomyolipoma, liver hepatic adenoma, liverhepatocellular carcinoma, lung small cell carcinoma, parotid glandpleomorphic adenoma, pleura malignant mesothelioma, schwannoma, smallintestine gastrointestinal stromal tumor (GIST), and thyroid glandpapillary carcinoma; breast carcinoma; chondrosarcoma; colonal or rectalcancer and a proliferative disease selected from bone giant cell tumorof bone, bone, non-ossifying fibroma, breast mucinous carcinoma, colonadenocarcinoma, colon adenoma, endometrium adenocarcinoma endometrioidtype, esophagus adenocarcinoma, kidney angiomyolipoma, kidney renal cellcarcinoma, liposarcoma, liver hepatocellular carcinoma, ovary granulosacell tumor, pancreas microcystic adenoma, pleura malignant mesothelioma,prostate benign nodular hyperplasia, spleen non-Hodgkin's lymphoma,stomach mucinous adenocarcinoma, thymus thymoma, malignant, thyroidgland nodular hyperplasia, urinary bladder, transitional cell carcinoma,and vulva squamous cell carcinoma; colon adenoma; esophagusadenocarcinoma; intestines malignant carcinoid tumor; intramuscularlipoma; kidney clear cell renal cell carcinoma and a proliferativedisease selected from adrenal gland, adrenal cortical carcinoma,endometrium adenocarcinoma endometrioid type, endometrium adenocarcinomaendometrioid type, kidney angiomyolipoma leiomyosarcoma, lipoma liverhepatocellular carcinoma, lymph node Hodgkin's disease, non-Hodgkin'slymphoma, pancreas adenocarcinoma, parotid gland pleomorphic adenoma,prostate adenocarcinoma, rectum adenocarcinoma, spleen chronic myeloidleukemia, spleen non-Hodgkin's lymphoma, and thyroid gland follicularadenoma; kidney oncocytoma; kidney polycystic kidney disease; kidneyrenal cell carcinoma; lipoma; liver hepatocellular carcinoma and aproliferative disease selected from, adrenal gland adrenal corticaladenoma, breast carcinoma, liver focal nodular hyperplasia, cancerrectum adenocarcinoma, cancer thyroid gland, nodular hyperplasia, cancerthyroid gland, papillary carcinoma, colon non-Hodgkin's lymphoma,endometrium hyperplasia, hepatic adenoma, kidney carcinoma, kidneyoncocytoma, lipoma, liposarcoma, liver focal nodular hyperplasia, liverhepatic adenoma, pleura malignant mesothelioma, neuroblastoma, pancreasadenocarcinoma, pancreas microcystic adenoma, parotid gland pleomorphicadenoma, pleura malignant mesothelioma, synovial sarcoma, thyroid glandnodular hyperplasia, and uterine cervix squamous cell carcinoma; lung,non-small cell lung carcinoma, and a proliferative disease selected frombreast carcinoma, chondrosarcoma, kidney oncocytoma, liverhepatocellular carcinoma, lung adenocarcinoma, lymph node Hodgkin'sdisease, lymph node non-Hodgkin's lymphoma, lymph node papillarycarcinoma of thyroid, omentum adenocarcinoma, ovary Mullerian mixedtumor, pancreas adenocarcinoma, testis mixed germ cell tumor, thymusthymoma benign, and thyroid gland, nodular hyperplasia; lymph nodeHodgkin's disease; lymph node papillary carcinoma of thyroid; lymph nodepapillary carcinoma of thyroid metastatic; myometrium leiomyoma;non-Hodgkin's lymphoma; non-Hodgkin's lymphoma, peripheral T cell typeor small lymphocytic type; pancreas adenocarcinoma and a proliferativedisease selected from bone giant cell tumor of bone, colonadenocarcinoma, fibromatosis, intramuscular lipoma, kidneyangiomyolipoma, kidney renal cell carcinoma, liver hepatic adenoma, lungadenocarcinoma, myometrium leiomyoma, non-Hodgkin's lymphoma smalllymphocytic type, pancreas adenocarcinoma, prostate benign nodularhyperplasia, rectum adenocarcinoma, spleen chronic myeloid leukemia, andthymus, thymoma, malignant; rectum adenocarcinoma; spleen chronicmyeloid leukemia; spleen extramedullary hematopoiesis; stomach,adenocarcinoma and a proliferative disease selected from, adrenal glandadrenal cortical adenoma, bone giant cell tumor of bone, bonenon-ossifying fibroma, breast carcinoma, colon adenocarcinoma, colonnon-Hodgkin's lymphoma, endometrium adenocarcinoma endometrioid, kidneyangiomyolipoma, kidney carcinoma, kidney oncocytoma, liver, focalnodular hyperplasia, liver hepatocellular carcinoma, lymph nodeHodgkin's disease, lymph node papillary carcinoma of thyroid, medullarycarcinoma of thyroid origin, metastatic adenocarcinoma of stomach,neurofibroma, ovary thecoma-fibroma, pancreas adenocarcinoma, pancreasmicrocystic adenoma, parathyroid gland adenoma, rectum adenocarcinoma,skin squamous cell carcinoma, spleen chronic myeloid leukemia, stomachgastrointestinal stromal tumor (GIST), thyroid gland nodularhyperplasia, thyroid gland papillary carcinoma, uterin cervix squamouscell carcinoma, and white blood cells chronic lymphocytic leukemia;stomach gastrointestinal stromal tumor (GIST); stomach cancer metastaticand a proliferative disease selected from adrenal gland adrenal corticalcarcinoma, thyroid gland papillary carcinoma, skin, squamous cellcarcinoma, breast carcinoma, colon adenocarcinoma, endometrium Mullerianmixed tumor, kidney carcinoma, leiomyosarcoma, lung neuroendocrinecarcinoma (non-small cell type), lymph node non-Hodgkin's lymphoma,non-Hodgkin's lymphoma, ovary Mullerian mixed tumor, pancreasadenocarcinoma, rectum adenocarcinoma, skin basal cell carcinoma,stomach gastrointestinal stromal tumor (GIST), and uterine cervixadenocarcinoma; testis seminoma; thymus benign thymoma; thyroid glandfollicular adenoma; and thyroid gland nodular hyperplasia.

Another preferred aspect of the present invention relates to the use ofthe peptides according to the present invention for the—preferablycombined—preferred immunotherapy of diseases according to the followingtable 4.

TABLE 4 Preferred peptides according to the present invention anddiseases to be treated Seq ID Sequence Tissue and disease 22 LEVEERTKPVlung, non-small cell lung carcinoma, breast, carcinoma 23 RDSPINANLRYlung, non-small cell lung carcinoma, breast, carcinoma 24 RPFVIVTA lung,non-small cell lung carcinoma, breast, carcinoma 25 RPIINTPMV lung,non-small cell lung carcinoma, breast, carcinoma 26 SPTSSRTSSL lung,non-small cell lung carcinoma, breast, carcinoma 27 ATSAPLVSR stomach,metastatic, lung, neuroendocrine carcinoma 114 YGNPRTNGM stomach,metastatic, breast, carcinoma 102 FSITKSVEL non-Hodgkin's lymphoma,small lymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, smalllymphocytic type 104 LSQEVCRD non-Hodgkin's lymphoma, small lymphocytictype 105 RDIQSPEQI non-Hodgkin's lymphoma, small lymphocytic type 106REDNSSNSL non-Hodgkin's lymphoma, small lymphocytic type 107 TEHQEPGLnon-Hodgkin's lymphoma, small lymphocytic type 108 TKNDLVVSLnon-Hodgkin's lymphoma, small lymphocytic type 977 AGREINLVDAHLKSE lymphnode, Hodgkin's disease 979 GREINLVDAHLKSE lymph node, Hodgkin's disease980 KPGIVYASLNHSVIG lymph node, Hodgkin's disease 220 RIHTGEKPYK colonor rectum, thyroid gland, nodular hyperplasia 53 APGSVLPRAL lymph node,Hodgkin's disease 54 DIKEHPLL lymph node, Hodgkin's disease 55 DSAGPQDARlymph node, Hodgkin's disease 56 FQYAKESYI lymph node, Hodgkin's disease57 KVLSWPFLM lymph node, Hodgkin's disease 58 LENDQSLSF lymph node,Hodgkin's disease 59 SPSRQPQV lymph node, Hodgkin's disease 60 SRHQSFTTKlymph node, Hodgkin's disease 61 SSHNASKTL lymph node, Hodgkin's disease1003 DNQYAVLENQKSSH colon or rectum, pleura, malignant mesothelioma,1004 GPPEIYSDTQFPS colon or rectum, pleura, malignant mesothelioma, 1005GPPEIYSDTQFPSLQ colon or rectum, pleura, malignant mesothelioma, 1006TPQGPPEIYSDTQFPS colon or rectum, pleura, malignant mesothelioma, 1007TPQGPPEIYSDTQFPSLQ colon or rectum, pleura, malignant mesothelioma, 1008TPQGPPEIYSDTQFPSLQST colon or rectum, pleura, malignant mesothelioma, 91EHADDDPSL kidney, Wilm's tumor 92 SEESVKSTTL kidney, Wilm's tumor 93SPRPPLGSSL kidney, Wilm's tumor 94 SPWWRSSL kidney, Wilm's tumor 95VYTPVDSLVF kidney, Wilm's tumor 18 DALLKRTM stomach, metastatic, skin,basal cell carcinoma 19 GEDVRSALL stomach, metastatic, skin, basal cellcarcinoma 20 KFAEEFYSF stomach, metastatic, skin, basal cell carcinoma21 YGYDNVKEY stomach, metastatic, skin, basal cell carcinoma 661EYVSLYHQPAAM non-Hodgkin's lymphoma, peripheral T cell type 664LPYLFQMPAYASSS non-Hodgkin's lymphoma, peripheral T cell type 665LPYLFQMPAYASSSK non-Hodgkin's lymphoma, peripheral T cell type 666NFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 667TNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 668TTNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 780DNGHLYREDQTSPAPG kidney, angiomyolipoma 781 DNGHLYREDQTSPAPGLR kidney,angiomyolipoma 782 EVQVFAPANALPARSE kidney, angiomyolipoma 783GHLYREDQTSPAPG kidney, angiomyolipoma 784 LPARSEAAAVQPVIG kidney,angiomyolipoma 785 NGHLYREDQTSPAPG kidney, angiomyolipoma 786NGHLYREDQTSPAPGL kidney, angiomyolipoma 787 NGHLYREDQTSPAPGLR kidney,angiomyolipoma 788 VFAPANALPARSEAA kidney, angiomyolipoma 789VQVFAPANALPARSE kidney, angiomyolipoma 178 HEIDRYTAI non-Hodgkin'slymphoma, follicular type, 179 VFTLKPLEF non-Hodgkin's lymphoma,follicular type, 180 YWVPRNAL non-Hodgkin's lymphoma, follicular type,694 DGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 695GELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 696NPSDGELIRTQPQRLP pancreas, adenocarcinoma, intramuscular lipoma 697NPSDGELIRTQPQRLPQ pancreas, adenocarcinoma, intramuscular lipoma 698NPSDGELIRTQPQRLPQL pancreas, adenocarcinoma, intramuscular lipoma 922FDFSQNTRVPRLPE non-Hodgkin's lymphoma, follicular type 923 GDAPAILFDKEFnon-Hodgkin's lymphoma, follicular type 924 VTHEIDRYTAIAY non-Hodgkin'slymphoma, follicular type 692 DAGSYKAQINQRNFE lymph node, non-Hodgkin'slymphoma 693 DAGSYKAQINQRNFEVT lymph node, non-Hodgkin's lymphoma 1AEHPNVTLTI spleen, non-Hodgkin's lymphoma 2 FLAEHPNVTL spleen,non-Hodgkin's lymphoma 4 EVAEFLARH spleen, non-Hodgkin's lymphoma 5RHSNVNLTI spleen, non-Hodgkin's lymphoma 222 QSTQRSLAL uterine cervix,squamous cell carcinoma 223 RDLQMNQALRF uterine cervix, squamous cellcarcinoma 224 RELESQLHVL uterine cervix, squamous cell carcinoma 225SEAEKLTLV uterine cervix, squamous cell carcinoma 6 HPDNVKLFL pancreas,adenocarcinoma, non-Hodgkin's lymphoma, small lymphocytic type 7ISDTGELKL pancreas, adenocarcinoma, non-Hodgkin's lymphoma, smalllymphocytic type 8 KVNGKLVALK pancreas, adenocarcinoma, non-Hodgkin'slymphoma, small lymphocytic type 9 NRLSAQAAL pancreas, pancreas,adenocarcinoma, non- Hodgkin's lymphoma, small lymphocytic type 10TPFTAIREA pancreas, pancreas, adenocarcinoma, non- Hodgkin's lymphoma,small lymphocytic type 11 FGLARAKSV kidney, clear cell renal cellcarcinoma, kidney, renal cell carcinoma, clear cell type 12 KIADFGLARbrain, glioblastoma, liver, hepatocellular carcinoma 812 DGSYRIFSKGASEcolon or rectum, liposarcoma 813 GSYRIFSKGASE colon or rectum,liposarcoma 814 SDGSYRIFSKGASE colon or rectum, liposarcoma 815SVKKMMKDNNLVRH colon or rectum, liver, hepatocellular carcinoma 816VKKMMKDNNLVRH colon or rectum, liver, hepatocellular carcinoma 145KITVPASQK colon, non-Hodgkin's lymphoma 146 KITVPASQKL colon,non-Hodgkin's lymphoma 147 VPASQKLRQL colon, non-Hodgkin's lymphoma 537ITARPVLW non-Hodgkin's lymphoma, diffuse large B-cell type 538KLMSPKLYVW non-Hodgkin's lymphoma, diffuse large B-cell type 539KVSAVTLAY non-Hodgkin's lymphoma, diffuse large B-cell type 540VEGSGELFRW non-Hodgkin's lymphoma, diffuse large B-cell type 672ADLSSFKSQELN lymph node, papillary carcinoma of thyroid, metastatic 673ADLSSFKSQELNER lymph node, papillary carcinoma of thyroid, metastatic674 ADLSSFKSQELNERN lymph node, papillary carcinoma of thyroid,metastatic 679 ISQELEELRAEQQR lymph node, papillary carcinoma ofthyroid, metastatic 680 ISQELEELRAEQQRLK lymph node, papillary carcinomaof thyroid, metastatic 681 KGTKQWVHARYA lymph node, papillary carcinomaof thyroid, metastatic 682 QADLSSFKSQELNER lymph node, papillarycarcinoma of thyroid, metastatic 684 TGSWIGLRNLDLKG lymph node,papillary carcinoma of thyroid, metastatic 743 AIVQAVSAHRHRnon-Hodgkin's lymphoma, peripheral T cell type 744 ARNFERNKAIKVInon-Hodgkin's lymphoma, peripheral T cell type 745 ARNFERNKAIKVIIAnon-Hodgkin's lymphoma, peripheral T cell type 746 NFERNKAIKVIInon-Hodgkin's lymphoma, peripheral T cell type 747 NFERNKAIKVIIAnon-Hodgkin's lymphoma, peripheral T cell type 748 VAIVQAVSAHRHnon-Hodgkin's lymphoma, peripheral T cell type 749 VAIVQAVSAHRHRnon-Hodgkin's lymphoma, peripheral T cell type 750 VAIVQAVSAHRHRAnon-Hodgkin's lymphoma, peripheral T cell type 818 VDKVLERDQKLSE lung,non-small cell lung carcinoma, lymph node, papillary carcinoma ofthyroid, metastatic 819 VDKVLERDQKLSELD lung, non-small cell lungcarcinoma, lymph node, papillary carcinoma of thyroid, metastatic 820VDKVLERDQKLSELDD lung, non-small cell lung carcinoma, lymph node,papillary carcinoma of thyroid, metastatic 821 VDKVLERDQKLSELDDRstomach, diffuse subtype adenocarcinoma, lymph node, papillary carcinomaof thyroid, metastatic 822 VLERDQKLSELDDR lung, non-small cell lungcarcinoma, lymph node, papillary carcinoma of thyroid, metastatic 833VDKVLERDQKLSE lung, non-small cell lung carcinoma, lymph node, papillarycarcinoma of thyroid, metastatic 834 VDKVLERDQKLSELD lung, non-smallcell lung carcinoma, lymph node, papillary carcinoma of thyroid,etastatic 835 VDKVLERDQKLSELDD lung, non-small cell lung carcinoma,lymph node, papillary carcinoma of thyroid, metastatic 836VDKVLERDQKLSELDDR stomach, diffuse subtype adenocarcinoma, lymph node,papillary carcinoma of thyroid, metastatic 837 VLERDQKLSELDDR lung,non-small cell lung carcinoma, lymph node, papillary carcinoma ofthyroid, metastatic 848 DDPAIDVCKKLLGKYPN kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 849 DKQPYSKLPGVSLLKP kidney, clearcell renal cell carcinoma, pancreas, adenocarcinoma 850DKQPYSKLPGVSLLKPL kidney, clear cell renal cell carcinoma, pancreas,adenocarcinoma 851 HPRYYISANVTGFK kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 852 SHPRYYISANVTG kidney, clear cellrenal cell carcinoma, pancreas, adenocarcinoma 853 SHPRYYISANVTGFKkidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma 854TSHPRYYISANVTG kidney, clear cell renal cell carcinoma, pancreas,adenocarcinoma 855 TSHPRYYISANVTGFK kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 908 DVGMFVALTKLGQPD stomach,differentiated subtype adenocarcinoma, uterine cervix, squamous cellcarcinoma, 909 VGMFVALTKLGQPD stomach, differentiated subtypeadenocarcinoma, uterine cervix, squamous cell carcinoma 1015GSSFFGELFNQNPE brain, glioblastoma, thyroid gland, papillary carcinoma1016 SGSSFFGELFNQNPE brain, glioblastoma, thyroid gland, papillarycarcinoma 466 DEMRFVTQI testis, mixed germ cell tumor 467 ETVHFATTQWtestis, mixed germ cell tumor 468 LPPPATQI testis, mixed germ cell tumor633 GNPAYRSFSNSLSQ kidney, angiomyolipoma 634 GPPGEAGYKAFSSLLA kidney,angiomyolipoma 635 GPPGEAGYKAFSSLLASS kidney, angiomyolipoma 636GPPGEAGYKAFSSLLASSA kidney, angiomyolipoma 637 GPPGEAGYKAFSSLLASSAkidney, angiomyolipoma VSPE 638 GPPGEAGYKAFSSLLASSA kidney,angiomyolipoma VSPEK 639 GYKAFSSLLASSAVSP kidney, angiomyolipoma 640GYKAFSSLLASSAVSPE kidney, angiomyolipoma 641 KAFSSLLASSAVSPE kidney,angiomyolipoma 642 NPAYRSFSNSLSQ kidney, angiomyolipoma 643SRDDFQEGREGIVAR kidney, angiomyolipoma 644 SSSSFHPAPGNAQ kidney,angiomyolipoma 645 VARLTESLFLDL kidney, angiomyolipoma 646VARLTESLFLDLLG kidney, angiomyolipoma 647 VIAGNPAYRSFSN kidney,angiomyolipoma 648 VPQPEPETWEQILRRNVLQ kidney, angiomyolipoma 649YKAFSSLLASSAVS kidney, angiomyolipoma 650 YKAFSSLLASSAVSP kidney,angiomyolipoma 651 YKAFSSLLASSAVSPE kidney, angiomyolipoma 992EDDYIKSWEDNQQGDE pleura, malignant mesothelioma 993 ELERIQIQEAAKKKPGpleura, malignant mesothelioma 994 ERIQIQEAAKKKP pleura, malignantmesothelioma 995 ERIQIQEAAKKKPG pleura, malignant mesothelioma 996ERIQIQEAAKKKPGI pleura, malignant mesothelioma 997 LERIQIQEAAKKKPGpleura, malignant mesothelioma 998 LSSISQYSGKIK pleura, malignantmesothelioma 941 EERNLLSVAYKNVVGAR colon or rectum, esophagus,adenocarcinoma, 942 ERNLLSVAYKNVVGAR colon or rectum, esophagus,adenocarcinoma, 943 IAELDTLSEESYKD colon or rectum, vulva, squamous cellcarcinoma, 944 IAELDTLSEESYKDS colon or rectum, vulva, squamous cellcarcinoma, 218 GDYGRAFNL stomach, metastatic, lymph node, non-Hodgkin'slymphoma, small lymphocytic type 219 TRHKIVHTK stomach, metastatic,lymph node, non-Hodgkin's lymphoma, small lymphocytic type 221 KAFNWFSTLstomach, metastatic, lymph node, non-Hodgkin's lymphoma, smalllymphocytic type 541 RPKSNIVL non-Hodgkin's lymphoma, diffuse largeB-cell type 542 RPKSNIVLL non-Hodgkin's lymphoma, diffuse large B-celltype 1001 INSRFPIPSATDPD brain, glioblastoma, brain, oligodendroglioma,1002 VQHYELLNGQSVFG brain, glioblastoma, brain, oligodendroglioma, 910AGVFHVEKNGRY stomach, diffuse subtype adenocarcinoma, colon,adenocarcinoma 911 FAGVFHVEKNGRYS stomach, diffuse subtypeadenocarcinoma, colon, adenocarcinoma 912 GPITITIVNRDGTR stomach,diffuse subtype adenocarcinoma, colon, adenocarcinoma 913 NGRYSISRTEAADLstomach, diffuse subtype adenocarcinoma, colon, adenocarcinoma 45DELPKFHQY stomach, adenocarcinoma, white blood cells, chroniclymphocytic leukemia 46 DVTGQFPSSF white blood cells, chroniclymphocytic leukemia 47 EHSRVLQQL white blood cells, chronic lymphocyticleukemia 48 IKVSKQLL white blood cells, chronic lymphocytic leukemia 49KPRQSSPQL white blood cells, chronic lymphocytic leukemia 50 KQLLAALEIwhite blood cells, chronic lymphocytic leukemia 51 RRKDLVLKY liver,focalnodular hyperplasia 52 RTRDYASLPPK white blood cells, chroniclymphocytic leukemia 124 GQKEALLKY liver, hepatocellular carcinoma,synovial sarcoma 125 KPSEERKTI liver, hepatocellular carcinoma, synovialsarcoma 126 KQTPKVLVV liver, hepatocellular carcinoma, synovial sarcoma127 SVIQHVQSF liver, hepatocellular carcinoma, synovial sarcoma 128TPIERIPYL liver, hepatocellular carcinoma, synovial sarcoma 773LPEFYKTVSPAL colon or rectum, endometrium, adenocarcinoma, endometrioidtype 774 VGQFIQDVKNSRST colon or rectum, endometrium, adenocarcinoma,endometrioid type 775 VGQFIQDVKNSRSTD colon or rectum, endometrium,adenocarcinoma, endometrioid type 776 VVGQFIQDVKNSRS colon or rectum,endometrium, adenocarcinoma, endometrioid type 777 VVGQFIQDVKNSRST colonor rectum, endometrium, adenocarcinoma, endometrioid type 778VVGQFIQDVKNSRSTD colon or rectum, endometrium, adenocarcinoma,endometrioid type 779 VVGQFIQDVKNSRSTDS colon or rectum, endometrium,adenocarcinoma, endometrioid type 685 FGNYNNQSSNFGPMKGGN pancreas,adenocarcinoma, thymus, thymoma, FGGRS malignant 686 FGPMKGGNFGGRSSGPYGpancreas, adenocarcinoma, thymus, thymoma, GGGQY malignant 687GPMKGGNFGGRSSGP pancreas, adenocarcinoma, thymus, thymoma, malignant 688GPYGGGGQYFAKP pancreas, adenocarcinoma, thymus, thymoma, malignant 689KGGNFGGRSSGP pancreas, adenocarcinoma, thymus, thymoma, malignant 690NDFGNYNNQSSNFGP pancreas, adenocarcinoma, thymus, thymoma, malignant 691SGPYGGGGQYFAKP pancreas, adenocarcinoma, thymus, thymoma, malignant 13AAANIIRTL liver, hepatocellular carcinoma, adrenal gland, adrenalcortical carcinoma 14 GRFKNLREAL liver, hepatocellular carcinoma,adrenal gland, adrenal cortical carcinoma, 15 MSPFSKATL liver,hepatocellular carcinoma, adrenal gland, adrenal cortical carcinoma, 16QEDPGDNQITL liver, hepatocellular carcinoma, adrenal gland, adrenalcortical carcinoma, 17 SPFSKATL liver, hepatocellular carcinoma, adrenalgland, adrenal cortical carcinoma, 129 AEVEKNETV kidney, clear cellrenal cell carcinoma, spleen, non-Hodgkin's lymphoma, follicular type130 EVKEEIPLV kidney, clear cell renal cell carcinoma, spleen,non-Hodgkin's lymphoma, follicular type 131 KPTSARSGL kidney, clear cellrenal cell carcinoma, spleen, non-Hodgkin's lymphoma, follicular type132 KYIETTPLTI kidney, clear cell renal cell carcinoma, spleen,non-Hodgkin's lymphoma, follicular type 133 SEIKTSIEV kidney, clear cellrenal cell carcinoma, spleen, non-Hodgkin's lymphoma, follicular type134 SVKPTSATK kidney, clear cell renal cell carcinoma, spleen,non-Hodgkin's lymphoma, follicular type 135 YPNKGVGQA kidney, clear cellrenal cell carcinoma, spleen, non-Hodgkin's lymphoma, follicular type966 ENNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 967NNEIISNIRDSVIN stomach, adenocarcinoma, kidney, oncocytoma 968SPTVQVFSASGKPV stomach, adenocarcinoma, kidney, oncocytoma 969SSPTVQVFSASGKPVE stomach, adenocarcinoma, kidney, oncocytoma 830DIMRVNVDKVLERDQK stomach, diffuse subtype adenocarcinoma, Medullarycarcinoma of thyroid Origin 831 DIMRVNVDKVLERDQKL stomach, diffusesubtype adenocarcinoma, medullary carcinoma 832 IMRVNVDKVLERDQK lung,non-small cell lung carcinoma, lymph node, Hodgkin's disease 752EEVITLIRSNQQLE pancreas, adenocarcinoma 753 EEVITLIRSNQQLEN pancreas,adenocarcinoma 754 IPADTFAALKNPNAML pancreas, adenocarcinoma 755LKQLLSDKQQKRQSG pancreas, adenocarcinoma 756 LKQLLSDKQQKRQSGQ pancreas,adenocarcinoma 118 DEHLLIQHY parotid gland, pleomorphic adenoma 119KQVASSTGF parotid gland, pleomorphic adenoma 120 RDFGPASQHFL parotidgland, pleomorphic adenoma 121 RQLGEVASF parotid gland, pleomorphicadenoma 122 TEAETTANVL parotid gland, pleomorphic adenoma 123 GYLPVQTVLkidney, clear cell renal cell carcinoma, parotid gland, pleomorphicadenoma 987 TRPYHSLPSEAVFA adrenal gland, adrenal cortical adenoma 988TRPYHSLPSEAVFAN adrenal gland, adrenal cortical adenoma 989 VAVFTFHNHGRTadrenal gland, adrenal cortical adenoma 990 VAVFTFHNHGRTA adrenal gland,adrenal cortical adenoma 991 VAVFTFHNHGRTANL adrenal gland, adrenalcortical adenoma 339 FLDPDIGGVAV kidney, clear cell renal cellcarcinoma, pancreas, adenocarcinoma 340 HTAPPENKTW kidney, clear cellrenal cell carcinoma, pancreas, adenocarcinoma 341 LLDTPVKTQY kidney,clear cell renal cell carcinoma, pancreas, adenocarcinoma 342 NAVKDFTSFkidney, clear cell renal cell carcinoma, pancreas, adenocarcinoma 343SGLLQIKKL kidney, clear cell renal cell carcinoma, pancreas,adenocarcinoma 344 YHDKNIVLL kidney, clear cell renal cell carcinoma,pancreas, adenocarcinoma 71 HLKSIPVSL kidney, clear cell renal cellcarcinoma, prostate, adenocarcinoma 72 KVWYNVENW kidney, clear cellrenal cell carcinoma, prostate, adenocarcinoma 73 LPAYRAQLL kidney,clear cell renal cell carcinoma, prostate, adenocarcinoma 74 LSEQTSVPLkidney, clear cell renal cell carcinoma, prostate, adenocarcinoma 75SLNQWLVSF kidney, clear cell renal cell carcinoma, prostate,adenocarcinoma 76 SMTSLAQKI kidney, clear cell renal cell carcinoma,prostate, adenocarcinoma 77 SSSGLHPPK kidney, clear cell renal cellcarcinoma, prostate, adenocarcinoma 578 GGGYGSGGGSGGYGSRRF colon orrectum, thymus, thymoma, malignant, 579 GGSFGGRSSGSP colon or rectum,thymus, thymoma, malignant 580 KGGSFGGRSSGSP colon or rectum, thymus,thymoma, malignant 581 SGQQQSNYGPMKGGSFGG colon or rectum, thymus,thymoma, malignant RSSGSPY 582 SGSPYGGGYGSGGGSGGY colon or rectum,thymus, thymoma, malignant GSRRF 583 SPYGGGYGSGGGSGGYGS colon or rectum,thymus, thymoma, malignant RRF 584 YGGGYGSGGGSGGYGSRRF colon or rectum,thymus, thymoma, malignant 84 VPVPHTTAL kidney, clear cell renal cellcarcinoma, endometrium, adenocarcinoma, endometrioid type 85 YQVLDVQRYkidney, clear cell renal cell carcinoma, endometrium, adenocarcinoma,endometrioid type 731 DGLNSLTYQVLDVQRYPL kidney, clear cell renal cellcarcinoma, endometrium, adenocarcinoma, endometrioid type 732HPVLQRQQLDYGIY kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 733 LNSLTYQVLDVQR kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 734LNSLTYQVLDVQRYP kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 735 LNSLTYQVLDVQRYPL kidney, clearcell renal cell carcinoma, endometrium, adenocarcinoma, endometrioidtype 736 LPQLVGVSTPLQG kidney, clear cell renal cell carcinoma,endometrium, adenocarcinoma, endometrioid type 737 LPQLVGVSTPLQGGkidney, clear cell renal cell carcinoma, endometrium, adenocarcinoma,endometrioid type 738 LPQLVGVSTPLQGGS kidney, clear cell renal cellcarcinoma, endometrium, adenocarcinoma, endometrioid type 739RLPQLVGVSTPLQGGS kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 740 SPHKVAIIIPFRNR kidney, clear cellrenal cell carcinoma, endometrium, adenocarcinoma, endometrioid type 741SPHKVAIIIPFRNRQE kidney, clear cell renal cell carcinoma, endometrium,adenocarcinoma, endometrioid type 742 SPHKVAIIIPFRNRQEH kidney, clearcell renal cell carcinoma, endometrium, adenocarcinoma, endometrioidtype 527 DEKQQHIVY liver, hepatocellular carcinoma, synovial sarcoma 528DEVYQVTVY liver, hepatocellular carcinoma, synovial sarcoma 529GEISEKAKL liver, hepatocellular carcinoma, synovial sarcoma 530YTMKEVLFY liver, hepatocellular carcinoma, synovial sarcoma 203GPRPITQSEL lymph node, non-Hodgkin's lymphoma, marginal zone B-cell type204 KPEPVDKVA lymph node, non-Hodgkin's lymphoma 205 TPSSRPASL lymphnode, non-Hodgkin's lymphoma 949 SPPQFRVNGAISN ovary, granulosa celltumor 950 SPPQFRVNGAISNFE ovary, granulosa cell tumor 951SPPQFRVNGAISNFEE ovary, granulosa cell tumor 952 SPPQFRVNGAISNFEEFovary, granulosa cell tumor 953 VGKMFVDVYFQEDKK ovary, granulosa celltumor 954 VGKmFVDVYFQEDKKE ovary, granulosa cell tumor 916EEFKKLTSIKIQNDK brain, glioblastoma, small intestine, gastrointestinalstromal tumor (GIST) 917 INRRMADDNKLFR brain, glioblastoma, smallintestine, gastrointestinal stromal tumor (GIST) 918 TATIVMVTNLKERKEbrain, glioblastoma, small intestine, gastrointestinal stromal tumor(GIST) 526 RINEFSISSF chondrosarcoma 585 GNRINEFSISSF chondrosarcoma 586HGNQITSDKVGRKV chondrosarcoma 587 IPPVNTNLENLYLQ chondrosarcoma 588LQVLRLDGNEIKR chondrosarcoma 589 LQVLRLDGNEIKRS chondrosarcoma 590LQVLRLDGNEIKRSA chondrosarcoma 592 LYVRLSHNSLTNNG chondrosarcoma 596WIALHGNQITSD chondrosarcoma 597 WIALHGNQITSDK chondrosarcoma 165ELNKLLEEI ovary, adenocarcinoma 166 IPFSNPRVL ovary, adenocarcinoma 167LLDEGAKLLY ovary, adenocarcinoma 168 SPADAHRNL ovary, adenocarcinoma 96APLQRSQSL kidney, renal cell carcinoma, clear cell type 97 DEVHQDTYkidney, renal cell carcinoma, clear cell type 98 LPHSATVTL kidney, renalcell carcinoma, clear cell type 152 APSEYRYTL stomach, mucinousadenocarcinoma 153 APSEYRYTLL stomach, mucinous adenocarcinoma 154EIFQNEVAR stomach, mucinous adenocarcinoma 155 KDVLIPGKL stomach,mucinous adenocarcinoma 156 VPLVREITF stomach, mucinous adenocarcinoma62 EEIDTTMRW liver, hepatocellular carcinoma, lipoma 63 ILDEKPVII liver,hepatocellular carcinoma, lipoma 64 LPQEPRTSL liver, hepatocellularcarcinoma, lipoma 65 LTYKLPVA liver, hepatocellular carcinoma, lipoma 66NEMELAHSSF liver, hepatocellular carcinoma, lipoma 67 REFPEANFEL liver,hepatocellular carcinoma, lipoma 68 THHIPDAKL liver, hepatocellularcarcinoma, lipoma 69 TVKENLSLF liver, hepatocellular carcinoma, lipoma70 VLLKKAVL liver, hepatocellular carcinoma, lipoma 136 ISMKILNSL lung,non-small cell lung carcinoma, thymus, thymoma 137 KTIAFLLPMF lung,non-small cell lung carcinoma, thymus, thymoma 138 RDSIINDF lung,non-small cell lung carcinoma, thymus, thymoma 139 SVKGGGGNEK lung,non-small cell lung carcinoma, thymus, thymoma 140 GIAKTGSGK lung,non-small cell lung carcinoma, thymus, thymoma 503 ALYATKTLR pancreas,microcystic adenoma 504 MEYVISRI pancreas, microcystic adenoma 505VPVGRQPII pancreas, microcystic adenoma 278 ATNGDLASR pancreas,adenocarcinoma, prostate, benign nodular hyperplasia 279 GLHAEVTGVGYpancreas, adenocarcinoma, prostate, benign nodular hyperplasia 280HVSSTSSSF pancreas, adenocarcinoma, prostate, benign nodular hyperplasia281 LQADLQNGL pancreas, adenocarcinoma, prostate, benign nodularhyperplasia 282 SELPVSEVA pancreas, adenocarcinoma, prostate, benignnodular hyperplasia 283 SQTKSVFEI pancreas, adenocarcinoma, prostate,benign nodular hyperplasia 284 THIFTSDGL pancreas, adenocarcinoma,prostate, benign nodular hyperplasia 285 VIYFPPLQK pancreas,adenocarcinoma, prostate, benign nodular hyperplasia 286 YPFSSEQKWpancreas, adenocarcinoma, prostate, benign nodular hyperplasia 78DLDVKKMPL kidney, carcinoma 79 FYTVIPHNF kidney, carcinoma 80 HHINTDNPSLkidney, carcinoma 81 RVGEVGQSK kidney, carcinoma 28 AELRSTASLL lipoma 29APASSHERASM lipoma 30 ASRQAPPHI lipoma 31 AVKKNPGIAA lipoma 32EEHLESHKKY lipoma 33 GEFTSARAV lipoma 34 GQSTPRLFSI lipoma 35 LVDDPLEYlipoma 36 RPKNLMQTL lipoma 37 RQAPPHIEL lipoma 38 SEAAELRSTA lipoma 490DSIGSTVSSER stomach, adenocarcinoma, signet ring cell type, 491LPYNNKDRDAL stomach, adenocarcinoma, signet ring cell type, 215DAMKRVEEI ovary, thecoma-fibroma 216 DIKEVKQNI ovary, thecoma-fibroma217 GPIYPGHGM ovary, thecoma-fibroma 963 GNTVIHLDQALARMR lung, smallcell carcinoma 964 NTVIHLDQALARMR lung, small cell carcinoma 965NTVIHLDQALARMRE lung, small cell carcinoma 187 AADTERLAL chondrosarcoma188 DMKAKVASL chondrosarcoma 189 HVLEEVQQV chondrosarcoma 190 KEAADTERLchondrosarcoma 191 RISEVLQKL chondrosarcoma 192 TEVRELVSL chondrosarcoma875 SVEEFLSEKLERI liver, hepatic adenoma 876 VEEFLSEKLERI liver, hepaticadenoma 973 ADDLEGEAFLPL spleen, chronic myeloid leukemia 974ADDLEGEAFLPLR spleen, chronic myeloid leukemia 975 ADDLEGEAFLPLREspleen, chronic myeloid leukemia 976 GADDLEGEAFLPLR spleen, chronicmyeloid leukemia 141 AETTDNVFTL kidney, clear cell renal cell carcinoma,thyroid gland, follicular adenoma 142 SEYQRFAVM kidney, clear cell renalcell carcinoma, thyroid gland, follicular adenoma 143 TFGERVVAF kidney,clear cell renal cell carcinoma, thyroid gland, follicular adenoma 144NENLVERF stomach, colon, adenocarcinoma, mucinous type 117 QLFSYAILGFliver, hepatocellular carcinoma, colon, non- Hodgkin's lymphoma 845GIRVAPVPLYNS lung, non-small cell lung carcinoma, liver, hepatocellularcarcinoma 846 GIRVAPVPLYNSFH lung, non-small cell lung carcinoma, liver,hepatocellular carcinoma 847 NPNGIRVAPVPLYNSFH lung, non-small cell lungcarcinoma, liver, hepatocellular carcinoma 478 AAVPVIISR lymph node,papillary carcinoma of thyroid, metastatic 479 EEIGKVAAA lymph node,papillary carcinoma of thyroid, metastatic 480 FLKDLVASV lymph node,papillary carcinoma of thyroid, metastatic 481 VIISRALEL lymph node,papillary carcinoma of thyroid, metastatic 420 QIDYKTLVL stomach,metastatic, leiomyosarcoma 421 VEDPTIVRI stomach, metastatic,leiomyosarcoma 543 GEPLSYTRFSLARQ lung, non-small cell lung carcinoma,lung, adenocarcinoma 544 GEPLSYTRFSLARQVD lung, non-small cell lungcarcinoma, lung, adenocarcinoma 545 GEPLSYTRFSLARQVDG lung, non-smallcell lung carcinoma, lung, adenocarcinoma 546 GGEPLSYTRFSLARQVD lung,non-small cell lung carcinoma, lung, adenocarcinoma 547GGEPLSYTRFSLARQVDG lung, non-small cell lung carcinoma, lung,adenocarcinoma 548 NPGGYVAYSKAATVTG lung, non-small cell lung carcinoma,lung, adenocarcinoma 549 NPGGYVAYSKAATVTGK lung, non-small cell lungcarcinoma, lung, adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-smallcell lung carcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung,non-small cell lung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLVlung, non-small cell lung carcinoma, lung, adenocarcinoma 553NSVIIVDKNGRLVY lung, non-small cell lung carcinoma, lung, adenocarcinoma554 RVEYHFLSPYVSPK lung, non-small cell lung carcinoma, lung,adenocarcinoma 555 RVEYHFLSPYVSPKE lung, non-small cell lung carcinoma,lung, adenocarcinoma 556 RVEYHFLSPYVSPKESPF lung, non-small cell lungcarcinoma, lung, adenocarcinoma 557 SPFRHVFWGSGSHTL lung, non-small celllung carcinoma, lung, adenocarcinoma 558 SVIIVDKNGRLV lung, non-smallcell lung carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung,non-small cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKElung, non-small cell lung carcinoma, lung, adenocarcinoma 388AEGPAGGFMVV spleen, chronic myeloid leukemia 389 AYYRDAEAY spleen,chronic myeloid leukemia 390 QVNRPLTMR spleen, chronic myeloid leukemia391 RHSPVFQVY spleen, chronic myeloid leukemia 392 SLPVPNSAY spleen,chronic myeloid leukemia 393 TLGPPGTAHLY spleen, chronic myeloidleukemia 308 VLYVGSKTK schwannoma 309 KTKEQVTNV schwannoma 310MPVDPDNEAY schwannoma 311 AEKTKQGVA schwannoma 446 EAFEFVKQR stomach,adenocarcinoma, breast, carcinoma 447 NHFEGHYQY stomach, adenocarcinoma,breast, carcinoma

Another more preferred aspect of the present invention relates to theuse of the peptides according to the present invention forthe—preferably combined—more preferred immunotherapy of diseasesaccording to the following table 5.

TABLE 5 More preferred peptides according to the present invention anddiseases to be treated Seq ID Sequence Tissue and disease 22 LEVEERTKPVbreast, carcinoma 23 RDSPINANLRY breast, carcinoma 24 RPFVIVTA breast,carcinoma 25 RPIINTPMV breast, carcinoma 26 SPTSSRTSSL breast, carcinoma27 ATSAPLVSR lung, neuroendocrine carcinoma 114 YGNPRTNGM breast,carcinoma 102 FSITKSVEL non-Hodgkin's lymphoma, small lymphocytic type103 GQTKNDLVV non-Hodgkin's lymphoma, small lymphocytic type 104LSQEVCRD non-Hodgkin's lymphoma, small lymphocytic type 105 RDIQSPEQInon-Hodgkin's lymphoma, small lymphocytic type 106 REDNSSNSLnon-Hodgkin's lymphoma, small lymphocytic type 107 TEHQEPGLnon-Hodgkin's lymphoma, small lymphocytic type 108 TKNDLVVSLnon-Hodgkin's lymphoma, small lymphocytic type 977 AGREINLVDAHLKSE lymphnode, Hodgkin's disease 978 AGREINLVDAHLKSEQT lymph node, Hodgkin'sdisease 979 GREINLVDAHLKSE lymph node, Hodgkin's disease 980KPGIVYASLNHSVIG lymph node, Hodgkin's disease 981 NKPGIVYASLNHSVIG lymphnode, Hodgkin's disease 982 TTLYVTDVKSASERPS lymph node, Hodgkin'sdisease 220 RIHTGEKPYK thyroid gland, nodular hyperplasia 53 APGSVLPRALlymph node, Hodgkin's disease 54 DIKEHPLL lymph node, Hodgkin's disease55 DSAGPQDAR lymph node, Hodgkin's disease 56 FQYAKESYI lymph node,Hodgkin's disease 57 KVLSWPFLM lymph node, Hodgkin's disease 58LENDQSLSF lymph node, Hodgkin's disease 59 SPSRQPQV lymph node,Hodgkin's disease 60 SRHQSFTTK lymph node, Hodgkin's disease 61SSHNASKTL lymph node, Hodgkin's disease 1003 DNQYAVLENQKSSH pleura,malignant mesothelioma 1004 GPPEIYSDTQFPS pleura, malignant mesothelioma1005 GPPEIYSDTQFPSLQ pleura, malignant mesothelioma 1006TPQGPPEIYSDTQFPS pleura, malignant mesothelioma 1007 TPQGPPEIYSDTQFPSLQpleura, malignant mesothelioma 1008 TPQGPPEIYSDTQFPSLQST pleura,malignant mesothelioma 91 EHADDDPSL kidney, Wilm's tumor 92 SEESVKSTTLkidney, Wilm's tumor 93 SPRPPLGSSL kidney, Wilm's tumor 94 SPWWRSSLkidney, Wilm's tumor 95 VYTPVDSLVF kidney, Wilm's tumor 18 DALLKRTMskin, basal cell carcinoma 19 GEDVRSALL skin, basal cell carcinoma 20KFAEEFYSF skin, basal cell carcinoma 21 YGYDNVKEY skin, basal cellcarcinoma 661 EYVSLYHQPAAM non-Hodgkin's lymphoma, peripheral T celltype, 662 IKAEYKGRVTLKQYPR non-Hodgkin's lymphoma, peripheral T celltype 663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral T cell type664 LPYLFQmPAYASSS non-Hodgkin's lymphoma, peripheral T cell type 665LPYLFQmPAYASSSK non-Hodgkin's lymphoma, peripheral T cell type 666NFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 667TNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 668TTNFIKAEYKGRVT non-Hodgkin's lymphoma, peripheral T cell type 669VTLNVHSEYEPSWEEQP non-Hodgkin's lymphoma, peripheral T cell type 670YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma, peripheral T cell type 671YPRKNLFLVEVTQLTESDSG non-Hodgkin's lymphoma, peripheral T cell type 780DNGHLYREDQTSPAPG kidney, angiomyolipoma 781 DNGHLYREDQTSPAPGLR kidney,angiomyolipoma 782 EVQVFAPANALPARSE kidney, angiomyolipoma 783GHLYREDQTSPAPG kidney, angiomyolipoma 784 LPARSEAAAVQPVIG kidney,angiomyolipoma 785 NGHLYREDQTSPAPG kidney, angiomyolipoma 786NGHLYREDQTSPAPGL kidney, angiomyolipoma 787 NGHLYREDQTSPAPGLR kidney,angiomyolipoma 788 VFAPANALPARSEAA kidney, angiomyolipoma 789VQVFAPANALPARSE kidney, angiomyolipoma 178 HEIDRYTAI non-Hodgkin'slymphoma 179 VFTLKPLEF non-Hodgkin's lymphoma 180 YWVPRNAL non-Hodgkin'slymphoma 694 DGELIRTQPQRLPQ intramuscular lipoma 695 GELIRTQPQRLPQintramuscular lipoma 696 NPSDGELIRTQPQRLP intramuscular lipoma 697NPSDGELIRTQPQRLPQ intramuscular lipoma 698 NPSDGELIRTQPQRLPQLintramuscular lipoma 922 FDFSQNTRVPRLPE non-Hodgkin's lymphoma 923GDAPAILFDKEF non-Hodgkin's lymphoma 924 VTHEIDRYTAIAY non-Hodgkin'slymphoma 692 DAGSYKAQINQRNFE lymph node, non-Hodgkin's lymphoma 693DAGSYKAQINQRNFEVT lymph node, non-Hodgkin's lymphoma 1 AEHPNVTLTIspleen, non-Hodgkin's lymphoma 2 FLAEHPNVTL spleen, non-Hodgkin'slymphoma 4 EVAEFLARH spleen, non-Hodgkin's lymphoma 5 RHSNVNLTI spleen,non-Hodgkin's lymphoma 222 QSTQRSLAL uterine cervix, squamous cellcarcinoma 223 RDLQMNQALRF uterine cervix, squamous cell carcinoma 224RELESQLHVL uterine cervix, squamous cell carcinoma 225 SEAEKLTLV uterinecervix, squamous cell carcinoma 6 HPDNVKLFL non-Hodgkin's lymphoma,small lymphocytic type 7 ISDTGELKL non-Hodgkin's lymphoma, smalllymphocytic type 8 KVNGKLVALK non-Hodgkin's lymphoma, small lymphocytictype 9 NRLSAQAAL non-Hodgkin's lymphoma, small lymphocytic type 10TPFTAIREA non-Hodgkin's lymphoma, small lymphocytic type 11 FGLARAKSVkidney, renal cell carcinoma, clear cell type 12 KIADFGLAR liver,hepatocellular carcinoma 812 DGSYRIFSKGASE liposarcoma 813 GSYRIFSKGASEliposarcoma 814 SDGSYRIFSKGASE liposarcoma 815 SVKKMMKDNNLVRH liver,hepatocellular carcinoma 816 VKKMMKDNNLVRH liver, hepatocellularcarcinoma 145 KITVPASQK colon, non-Hodgkin's lymphoma 146 KITVPASQKLcolon, non-Hodgkin's lymphoma 147 VPASQKLRQL colon, non-Hodgkin'slymphoma 537 ITARPVLW non-Hodgkin's lymphoma, diffuse large B-cell type538 KLMSPKLYVW non-Hodgkin's lymphoma, diffuse large B-cell type 539KVSAVTLAY non-Hodgkin's lymphoma, diffuse large B-cell type 540VEGSGELFRW non-Hodgkin's lymphoma, diffuse large B-cell type 672ADLSSFKSQELN lymph node, papillary carcinoma of thyroid, metastatic 673ADLSSFKSQELNER lymph node, papillary carcinoma of thyroid, metastatic674 ADLSSFKSQELNERN lymph node, papillary carcinoma of thyroid,metastatic 675 ADLSSFKSQELNERNE lymph node, papillary carcinoma ofthyroid, metastatic 676 ADLSSFKSQELNERNEA lymph node, papillarycarcinoma of thyroid, metastatic 677 AEQQRLKSQDLELSWNLNG lymph node,papillary carcinoma of thyroid, metastatic 678 EQQRLKSQDLELSWN lymphnode, papillary carcinoma of thyroid, metastatic 679 ISQELEELRAEQQRlymph node, papillary carcinoma of thyroid, metastatic 680ISQELEELRAEQQRLK lymph node, papillary carcinoma of thyroid, metastatic681 KGTKQWVHARYA lymph node, papillary carcinoma of thyroid, metastatic682 QADLSSFKSQELNER lymph node, papillary carcinoma of thyroid,metastatic 683 SWNLNGLQADLSSFK lymph node, papillary carcinoma ofthyroid, metastatic 684 TGSWIGLRNLDLKG lymph node, papillary carcinomaof thyroid, metastatic 743 AIVQAVSAHRHR non-Hodgkin's lymphoma,peripheral T cell type 744 ARNFERNKAIKVI non-Hodgkin's lymphoma,peripheral T cell type 745 ARNFERNKAIKVIIA non-Hodgkin's lymphoma,peripheral T cell type 746 NFERNKAIKVII non-Hodgkin's lymphoma,peripheral T cell type 747 NFERNKAIKVIIA non-Hodgkin's lymphoma,peripheral T cell type 748 VAIVQAVSAHRH non-Hodgkin's lymphoma,peripheral T cell type 749 VAIVQAVSAHRHR non-Hodgkin's lymphoma,peripheral T cell type 750 VAIVQAVSAHRHRA non-Hodgkin's lymphoma,peripheral T cell type 751 VAIVQAVSAHRHRAR non-Hodgkin's lymphoma,peripheral T cell type 818 VDKVLERDQKLSE lymph node, papillary carcinomaof thyroid, metastatic 819 VDKVLERDQKLSELD lymph node, papillarycarcinoma of thyroid, metastatic 820 VDKVLERDQKLSELDD lymph node,papillary carcinoma of thyroid, metastatic 821 VDKVLERDQKLSELDDR lymphnode, papillary carcinoma of thyroid, metastatic 822 VLERDQKLSELDDRlymph node, papillary carcinoma of thyroid, metastatic 833 VDKVLERDQKLSElymph node, papillary carcinoma of thyroid, metastatic 834VDKVLERDQKLSELD lymph node, papillary carcinoma of thyroid, metastatic835 VDKVLERDQKLSELDD lymph node, papillary carcinoma of thyroid,metastatic 836 VDKVLERDQKLSELDDR lymph node, papillary carcinoma ofthyroid, metastatic 837 VLERDQKLSELDDR lymph node, papillary carcinomaof thyroid, metastatic 848 DDPAIDVCKKLLGKYPN pancreas, adenocarcinoma849 DKQPYSKLPGVSLLKP pancreas, adenocarcinoma 850 DKQPYSKLPGVSLLKPLpancreas, adenocarcinoma 851 HPRYYISANVTGFK pancreas, adenocarcinoma 852SHPRYYISANVTG pancreas, adenocarcinoma 853 SHPRYYISANVTGFK pancreas,adenocarcinoma 854 TSHPRYYISANVTG pancreas, adenocarcinoma 855TSHPRYYISANVTGFK pancreas, adenocarcinoma 908 DVGMFVALTKLGQPD uterinecervix, squamous cell carcinoma 909 VGmFVALTKLGQPD uterine cervix,squamous cell carcinoma 1015 GSSFFGELFNQNPE thyroid gland, papillarycarcinoma 1016 SGSSFFGELFNQNPE thyroid gland, papillary carcinoma 466DEMRFVTQI testis, mixed germ cell tumor 467 ETVHFATTQW testis, mixedgerm cell tumor 468 LPPPATQI testis, mixed germ cell tumor 633GNPAYRSFSNSLSQ kidney, angiomyolipoma 634 GPPGEAGYKAFSSLLA kidney,angiomyolipoma 635 GPPGEAGYKAFSSLLASS kidney, angiomyolipoma 636GPPGEAGYKAFSSLLASSA kidney, angiomyolipoma 637 GPPGEAGYKAFSSLLASSkidney, angiomyolipoma AVSPE 639 GYKAFSSLLASSAVSP kidney, angiomyolipoma640 GYKAFSSLLASSAVSPE kidney, angiomyolipoma 641 KAFSSLLASSAVSPE kidney,angiomyolipoma 642 NPAYRSFSNSLSQ kidney, angiomyolipoma 643SRDDFQEGREGIVAR kidney, angiomyolipoma 644 SSSSFHPAPGNAQ kidney,angiomyolipoma 645 VARLTESLFLDL kidney, angiomyolipoma 646VARLTESLFLDLLG kidney, angiomyolipoma 647 VIAGNPAYRSFSN kidney,angiomyolipoma 648 VPQPEPETVVEQILRRNVLQ kidney, angiomyolipoma 649YKAFSSLLASSAVS kidney, angiomyolipoma 650 YKAFSSLLASSAVSP kidney,angiomyolipoma 651 YKAFSSLLASSAVSPE kidney, angiomyolipoma 992EDDYIKSWEDNQQGDE pleura, malignant mesothelioma 993 ELERIQIQEAAKKKPGpleura, malignant mesothelioma 994 ERIQIQEAAKKKP pleura, malignantmesothelioma 995 ERIQIQEAAKKKPG pleura, malignant mesothelioma 996ERIQIQEAAKKKPGI pleura, malignant mesothelioma 997 LERIQIQEAAKKKPGpleura, malignant mesothelioma 998 LSSISQYSGKIK pleura, malignantmesothelioma, 941 EERNLLSVAYKNVVGAR esophagus, adenocarcinoma 942ERNLLSVAYKNVVGAR esophagus, adenocarcinoma 943 IAELDTLSEESYKD vulva,squamous cell carcinoma 944 IAELDTLSEESYKDS vulva, squamous cellcarcinoma 218 GDYGRAFNL stomach, metastatic, lymph node, non-Hodgkin'slymphoma, small lymphocytic type 219 TRHKIVHTK stomach, metastatic,lymph node, non-Hodgkin's lymphoma, small lymphocytic type 221 KAFNWFSTLstomach, metastatic, lymph node, non-Hodgkin's lymphoma, smalllymphocytic type 541 RPKSNIVL non-Hodgkin's lymphoma, diffuse largeB-cell type 542 RPKSNIVLL non-Hodgkin's lymphoma, diffuse large B-celltype 1001 INSRFPIPSATDPD brain, glioblastoma, brain, oligodendroglioma,1002 VQHYELLNGQSVFG brain, glioblastoma, brain, oligodendroglioma, 910AGVFHVEKNGRY colon, adenocarcinoma, mucinous type 911 FAGVFHVEKNGRYScolon, adenocarcinoma, mucinous type 912 GPITITIVNRDGTR colon,adenocarcinoma, mucinous type 913 NGRYSISRTEAADL colon, adenocarcinoma,mucinous type 45 DELPKFHQY white blood cells, chronic lymphocyticleukemia 46 DVTGQFPSSF white blood cells, chronic lymphocytic leukemia47 EHSRVLQQL white blood cells, chronic lymphocytic leukemia 48 IKVSKQLLwhite blood cells, chronic lymphocytic leukemia 49 KPRQSSPQL white bloodcells, chronic lymphocytic leukemia 50 KQLLAALEI white blood cells,chronic lymphocytic leukemia 51 RRKDLVLKY liver, focalnodularhyperplasia 52 RTRDYASLPPK white blood cells, chronic lymphocyticleukemia 124 GQKEALLKY synovial sarcoma 125 KPSEERKTI synovial sarcoma126 KQTPKVLVV synovial sarcoma 127 SVIQHVQSF synovial sarcoma 128TPIERIPYL synovial sarcoma 773 LPEFYKTVSPAL endometrium, adenocarcinoma,endometrioid type 774 VGQFIQDVKNSRST endometrium, adenocarcinoma,endometrioid type 775 VGQFIQDVKNSRSTD endometrium, adenocarcinoma,endometrioid type 776 VVGQFIQDVKNSRS endometrium, adenocarcinoma,endometrioid type 777 VVGQFIQDVKNSRST endometrium, adenocarcinoma,endometrioid type 778 VVGQFIQDVKNSRSTD endometrium, adenocarcinoma,endometrioid type 779 VVGQFIQDVKNSRSTDS endometrium, adenocarcinoma,endometrioid type 687 GPMKGGNFGGRSSGP thymus, thymoma, malignant 688GPYGGGGQYFAKP thymus, thymoma, malignant 689 KGGNFGGRSSGP thymus,thymoma, malignant 690 NDFGNYNNQSSNFGP thymus, thymoma, malignant 691SGPYGGGGQYFAKP thymus, thymoma, malignant 13 AAANIIRTL adrenal gland,adrenal cortical carcinoma 14 GRFKNLREAL adrenal gland, adrenal corticalcarcinoma 15 MSPFSKATL adrenal gland, adrenal cortical carcinoma 16QEDPGDNQITL adrenal gland, adrenal cortical carcinoma 17 SPFSKATLadrenal gland, adrenal cortical carcinoma 129 AEVEKNETV spleen,non-Hodgkin's lymphoma 130 EVKEEIPLV spleen, non-Hodgkin's lymphoma 131KPTSARSGL spleen, non-Hodgkin's lymphoma 132 KYIETTPLTI spleen,non-Hodgkin's lymphoma 133 SEIKTSIEV spleen, non-Hodgkin's lymphoma 134SVKPTSATK spleen, non-Hodgkin's lymphoma 135 YPNKGVGQA spleen,non-Hodgkin's lymphoma 966 ENNEIISNIRDSVIN kidney, oncocytoma 967NNEIISNIRDSVIN kidney, oncocytoma 968 SPTVQVFSASGKPV kidney, oncocytoma969 SSPTVQVFSASGKPVE kidney, oncocytoma 830 DIMRVNVDKVLERDQK Medullarycarcinoma of thyroid origin 831 DIMRVNVDKVLERDQKL Medullary carcinoma ofthyroid origin 832 IMRVNVDKVLERDQK lymph node, Hodgkin's disease 752EEVITLIRSNQQLE pancreas, adenocarcinoma, 753 EEVITLIRSNQQLEN pancreas,adenocarcinoma, 754 IPADTFAALKNPNAML pancreas, adenocarcinoma 755LKQLLSDKQQKRQSG pancreas, adenocarcinoma 756 LKQLLSDKQQKRQSGQ pancreas,adenocarcinoma 339 FLDPDIGGVAV pancreas, adenocarcinoma 340 HTAPPENKTWpancreas, adenocarcinoma 341 LLDTPVKTQY pancreas, adenocarcinoma 342NAVKDFTSF pancreas, adenocarcinoma 343 SGLLQIKKL pancreas,adenocarcinoma 344 YHDKNIVLL pancreas, adenocarcinoma 71 HLKSIPVSLprostate, adenocarcinoma 72 KVWYNVENW prostate, adenocarcinoma 73LPAYRAQLL prostate, adenocarcinoma 74 LSEQTSVPL prostate, adenocarcinoma75 SLNQWLVSF prostate, adenocarcinoma 76 SMTSLAQKI prostate,adenocarcinoma 77 SSSGLHPPK prostate, adenocarcinoma 578GGGYGSGGGSGGYGSRRF thymus, thymoma, malignant 579 GGSFGGRSSGSP thymus,thymoma, malignant 580 KGGSFGGRSSGSP thymus, thymoma, malignant 583SPYGGGYGSGGGSGGYG thymus, thymoma, malignant SRRF 584 YGGGYGSGGGSGGYGSRthymus, thymoma, malignant RF 84 VPVPHTTAL endometrium, adenocarcinoma85 YQVLDVQRY endometrium, adenocarcinoma 731 DGLNSLTYQVLDVQRYPLendometrium, adenocarcinoma 732 HPVLQRQQLDYGIY endometrium,adenocarcinoma 733 LNSLTYQVLDVQR endometrium, adenocarcinoma 734LNSLTYQVLDVQRYP endometrium, adenocarcinoma 735 LNSLTYQVLDVQRYPLendometrium, adenocarcinoma 736 LPQLVGVSTPLQG endometrium,adenocarcinoma 737 LPQLVGVSTPLQGG endometrium, adenocarcinoma 738LPQLVGVSTPLQGGS endometrium, adenocarcinoma 739 RLPQLVGVSTPLQGGSendometrium, adenocarcinoma 740 SPHKVAIIIPFRNR endometrium,adenocarcinoma 741 SPHKVAIIIPFRNRQE endometrium, adenocarcinoma 742SPHKVAIIIPFRNRQEH endometrium, adenocarcinoma 527 DEKQQHIVY synovialsarcoma 528 DEVYQVTVY synovial sarcoma 529 GEISEKAKL synovial sarcoma530 YTMKEVLFY synovial sarcoma 203 GPRPITQSEL lymph node, non-Hodgkin'slymphoma, marginal Zone B-cell type 204 KPEPVDKVA lymph node,non-Hodgkin's lymphoma, marginal Zone B-cell type 205 TPSSRPASL lymphnode, non-Hodgkin's lymphoma, marginal Zone B-cell type 949SPPQFRVNGAISN ovary, granulosa cell tumor 950 SPPQFRVNGAISNFE ovary,granulosa cell tumor 951 SPPQFRVNGAISNFEE ovary, granulosa cell tumor952 SPPQFRVNGAISNFEEF ovary, granulosa cell tumor 953 VGKMFVDVYFQEDKKovary, granulosa cell tumor 954 VGKmFVDVYFQEDKKE ovary, granulosa celltumor 916 EEFKKLTSIKIQNDK small intestine, gastrointestinal stromaltumor (GIST) 917 INRRMADDNKLFR small intestine, gastrointestinal stromaltumor (GIST) 918 TATIVMVTNLKERKE small intestine, gastrointestinalstromal tumor (GIST) 526 RINEFSISSF connective tissues, chondrosarcoma585 GNRINEFSISSF connective tissues, chondrosarcoma 586 HGNQITSDKVGRKVconnective tissues, chondrosarcoma 587 IPPVNTNLENLYLQ connectivetissues, chondrosarcoma 588 LQVLRLDGNEIKR connective tissues,chondrosarcoma 589 LQVLRLDGNEIKRS connective tissues, chondrosarcoma 590LQVLRLDGNEIKRSA connective tissues, chondrosarcoma 591 LRELHLDHNQISRVPNconnective tissues, chondrosarcoma 592 LYVRLSHNSLTNNG connectivetissues, chondrosarcoma, 593 VPSRMKYVYFQNNQ connective tissues,chondrosarcoma 594 VPSRMKYVYFQNNQIT connective tissues, chondrosarcoma595 VPSRMKYVYFQNNQITS connective tissues, chondrosarcoma 596WIALHGNQITSD connective tissues, chondrosarcoma 597 WIALHGNQITSDKconnective tissues, chondrosarcoma 165 ELNKLLEEI ovary, adenocarcinoma,endometrioid type 166 IPFSNPRVL ovary, adenocarcinoma, endometrioid type167 LLDEGAKLLY ovary, adenocarcinoma, endometrioid type 168 SPADAHRNLovary, adenocarcinoma, endometrioid type 96 APLQRSQSL kidney, renal cellcarcinoma, clear cell type 97 DEVHQDTY kidney, renal cell carcinoma,clear cell type 98 LPHSATVTL kidney, renal cell carcinoma, clear celltype 152 APSEYRYTL stomach, mucinous adenocarcinoma 153 APSEYRYTLLstomach, mucinous adenocarcinoma 154 EIFQNEVAR stomach, mucinousadenocarcinoma 155 KDVLIPGKL stomach, mucinous adenocarcinoma 156VPLVREITF stomach, mucinous adenocarcinoma 136 ISMKILNSL thymus,thymoma, benign 137 KTIAFLLPMF thymus, thymoma, benign 138 RDSIINDFthymus, thymoma, benign 139 SVKGGGGNEK thymus, thymoma, benign 140GIAKTGSGK thymus, thymoma, benign 503 ALYATKTLR pancreas, microcysticadenoma 504 MEYVISRI pancreas, microcystic adenoma 505 VPVGRQPIIpancreas, microcystic adenoma 278 ATNGDLASR prostate, benign nodularhyperplasia 279 GLHAEVTGVGY prostate, benign nodular hyperplasia 280HVSSTSSSF prostate, benign nodular hyperplasia 281 LQADLQNGL prostate,benign nodular hyperplasia 282 SELPVSEVA prostate, benign nodularhyperplasia 283 SQTKSVFEI prostate, benign nodular hyperplasia 284THIFTSDGL prostate, benign nodular hyperplasia 285 VIYFPPLQK prostate,benign nodular hyperplasia 286 YPFSSEQKW prostate, benign nodularhyperplasia 963 GNTVIHLDQALARMR lung, small cell carcinoma 964NTVIHLDQALARMR lung, small cell carcinoma 965 NTVIHLDQALARMRE lung,small cell carcinoma 187 AADTERLAL connective tissues, chondrosarcoma188 DMKAKVASL connective tissues, chondrosarcoma 189 HVLEEVQQVconnective tissues, chondrosarcoma 190 KEAADTERL connective tissues,chondrosarcoma 191 RISEVLQKL connective tissues, chondrosarcoma 192TEVRELVSL 973 ADDLEGEAFLPL spleen, chronic myeloid leukemia 974ADDLEGEAFLPLR spleen, chronic myeloid leukemia 975 ADDLEGEAFLPLREspleen, chronic myeloid leukemia 976 GADDLEGEAFLPLR spleen, chronicmyeloid leukemia 141 AETTDNVFTL thyroid gland, follicular adenoma 142SEYQRFAVM thyroid gland, follicular adenoma 143 TFGERVVAF thyroid gland,follicular adenoma 144 NENLVERF stomach, colon, adenocarcinoma, mucinoustype 117 QLFSYAILGF colon, non-Hodgkin's lymphoma 845 GIRVAPVPLYNS lung,non-small cell lung carcinoma, liver, hepatocellular carcinoma 846GIRVAPVPLYNSFH lung, non-small cell lung carcinoma, liver,hepatocellular carcinoma 847 NPNGIRVAPVPLYNSFH lung, non-small cell lungcarcinoma, liver, hepatocellular carcinoma 478 AAVPVIISR lymph node,papillary carcinoma of thyroid, metastatic 479 EEIGKVAAA lymph node,papillary carcinoma of thyroid, metastatic 480 FLKDLVASV lymph node,papillary carcinoma of thyroid, metastatic 481 VIISRALEL lymph node,papillary carcinoma of thyroid, metastatic 420 QIDYKTLVL leiomyosarcoma421 VEDPTIVRI leiomyosarcoma 543 GEPLSYTRFSLARQ lung, non-small celllung carcinoma, lung, adenocarcinoma 544 GEPLSYTRFSLARQVD lung,non-small cell lung carcinoma, lung, adenocarcinoma 545GEPLSYTRFSLARQVDG lung, non-small cell lung carcinoma, lung,adenocarcinoma 546 GGEPLSYTRFSLARQVD lung, non-small cell lungcarcinoma, lung, adenocarcinoma 547 GGEPLSYTRFSLARQVDG lung, non-smallcell lung carcinoma, lung, adenocarcinoma 548 NPGGYVAYSKAATVTG lung,non-small cell lung carcinoma, lung, adenocarcinoma 549NPGGYVAYSKAATVTGK lung, non-small cell lung carcinoma, lung,adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-small cell lungcarcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small celllung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung, non-smallcell lung carcinoma, lung, adenocarcinoma 553 NSVIIVDKNGRLVY lung,non-small cell lung carcinoma, lung, adenocarcinoma 554 RVEYHFLSPYVSPKlung, non-small cell lung carcinoma, lung, adenocarcinoma 555RVEYHFLSPYVSPKE lung, non-small cell lung carcinoma, lung,adenocarcinoma 556 RVEYHFLSPYVSPKESPF lung, non-small cell lungcarcinoma, lung, adenocarcinoma 557 SPFRHVFWGSGSHTL lung, non-small celllung carcinoma, lung, adenocarcinoma 558 SVIIVDKNGRLV lung, non-smallcell lung carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung,non-small cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKElung, non-small cell lung carcinoma, lung, adenocarcinoma 388AEGPAGGFmVV spleen, chronic myeloid leukemia 389 AYYRDAEAY spleen,chronic myeloid leukemia 390 QVNRPLTMR spleen, chronic myeloid leukemia391 RHSPVFQVY spleen, chronic myeloid leukemia 392 SLPVPNSAY spleen,chronic myeloid leukemia 393 TLGPPGTAHLY spleen, chronic myeloidleukemia 308 VLYVGSKTK schwannoma 309 KTKEQVTNV schwannoma 310MPVDPDNEAY schwannoma 311 AEKTKQGVA schwannoma 446 EAFEFVKQR stomach,diffuse subtype adenocarcinoma, breast, carcinoma 447 NHFEGHYQY stomach,diffuse subtype adenocarcinoma, breast, carcinoma

Finally a most preferred aspect of the present invention relates to theuse of the peptides according to the present invention forthe—preferably combined—most preferred immunotherapy of diseasesaccording to the following table 6.

TABLE 6 Most preferred peptides according to the present invention anddiseases to be treated Seq ID Sequence Tissue and disease 22 LEVEERTKPVbreast, carcinoma 23 RDSPINANLRY breast, carcinoma 24 RPFVIVTA breast,carcinoma 25 RPIINTPMV breast, carcinoma 26 SPTSSRTSSL breast, carcinoma27 ATSAPLVSR lung, neuroendocrine carcinoma (non-small cell type) 114YGNPRTNGM breast, carcinoma 102 FSITKSVEL non-Hodgkin's lymphoma, smalllymphocytic type 103 GQTKNDLVV non-Hodgkin's lymphoma, small lymphocytictype 104 LSQEVCRD non-Hodgkin's lymphoma, small lymphocytic type 105RDIQSPEQI non-Hodgkin's lymphoma, small lymphocytic type 106 REDNSSNSLnon-Hodgkin's lymphoma, small lymphocytic type 107 TEHQEPGLnon-Hodgkin's lymphoma, small lymphocytic type 108 TKNDLVVSLnon-Hodgkin's lymphoma, small lymphocytic type 977 AGREINLVDAHLKSE lymphnode, Hodgkin's disease 978 AGREINLVDAHLKSEQT lymph node, Hodgkin'sdisease 979 GREINLVDAHLKSE lymph node, Hodgkin's disease 980KPGIVYASLNHSVIG lymph node, Hodgkin's disease 981 NKPGIVYASLNHSVIG lymphnode, Hodgkin's disease 982 TTLYVTDVKSASERPS lymph node, Hodgkin'sdisease 220 RIHTGEKPYK colon or rectum, thyroid gland, nodularhyperplasia 53 APGSVLPRAL lymph node, Hodgkin's disease 54 DIKEHPLLlymph node, Hodgkin's disease 55 DSAGPQDAR lymph node, Hodgkin's disease56 FQYAKESYI lymph node, Hodgkin's disease 57 KVLSWPFLM lymph node,Hodgkin's disease 58 LENDQSLSF lymph node, Hodgkin's disease 59 SPSRQPQVlymph node, Hodgkin's disease 60 SRHQSFTTK lymph node, Hodgkin's disease61 SSHNASKTL lymph node, Hodgkin's disease 1003 DNQYAVLENQKSSH pleura,malignant mesothelioma 1004 GPPEIYSDTQFPS pleura, malignant mesothelioma1005 GPPEIYSDTQFPSLQ pleura, malignant mesothelioma 1006TPQGPPEIYSDTQFPS pleura, malignant mesothelioma 1007 TPQGPPEIYSDTQFPSLQpleura, malignant mesothelioma 1008 TPQGPPEIYSDTQFPSLQST pleura,malignant mesothelioma 661 EYVSLYHQPAAM non-Hodgkin's lymphoma,peripheral T cell type 662 IKAEYKGRVTLKQYPR non-Hodgkin's lymphoma,peripheral T cell type 663 LNVHSEYEPSWEEQP non-Hodgkin's lymphoma,peripheral T cell type 664 LPYLFQMPAYASSS non-Hodgkin's lymphoma,peripheral T cell type 665 LPYLFQMPAYASSSK non-Hodgkin's lymphoma,peripheral T cell type 666 NFIKAEYKGRVT non-Hodgkin's lymphoma,peripheral T cell type 667 TNFIKAEYKGRVT non-Hodgkin's lymphoma,peripheral T cell type 668 TTNFIKAEYKGRVT non-Hodgkin's lymphoma,peripheral T cell type 669 VTLNVHSEYEPSWEEQP non-Hodgkin's lymphoma,peripheral T cell type 670 YPRKNLFLVEVTQLTESDS non-Hodgkin's lymphoma,peripheral T cell type 671 YPRKNLFLVEVTQLTESDSG non-Hodgkin's lymphoma,peripheral T cell type 780 DNGHLYREDQTSPAPG kidney, angiomyolipoma 781DNGHLYREDQTSPAPGLR kidney, angiomyolipoma 782 EVQVFAPANALPARSE kidney,angiomyolipoma 783 GHLYREDQTSPAPG kidney, angiomyolipoma 784LPARSEAAAVQPVIG kidney, angiomyolipoma 785 NGHLYREDQTSPAPG kidney,angiomyolipoma 786 NGHLYREDQTSPAPGL kidney, angiomyolipoma 787NGHLYREDQTSPAPGLR kidney, angiomyolipoma 788 VFAPANALPARSEAA kidney,angiomyolipoma 789 VQVFAPANALPARSE kidney, angiomyolipoma 222 QSTQRSLALuterine cervix, squamous cell carcinoma 223 RDLQMNQALRF uterine cervix,squamous cell carcinoma 224 RELESQLHVL uterine cervix, squamous cellcarcinoma 225 SEAEKLTLV uterine cervix, squamous cell carcinoma 12KIADFGLAR liver, hepatocellular carcinoma 812 DGSYRIFSKGASE colon orrectum 813 GSYRIFSKGASE colon or rectum 814 SDGSYRIFSKGASE colon orrectum 815 SVKKMMKDNNLVRH colon or rectum, liver, hepatocellularcarcinoma 816 VKKMMKDNNLVRH colon or rectum, liver, hepatocellularcarcinoma 743 AIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T celltype 744 ARNFERNKAIKVI non-Hodgkin's lymphoma, peripheral T cell type745 ARNFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 746NFERNKAIKVII non-Hodgkin's lymphoma, peripheral T cell type 747NFERNKAIKVIIA non-Hodgkin's lymphoma, peripheral T cell type 748VAIVQAVSAHRH non-Hodgkin's lymphoma, peripheral T cell type 749VAIVQAVSAHRHR non-Hodgkin's lymphoma, peripheral T cell type 750VAIVQAVSAHRHRA non-Hodgkin's lymphoma, peripheral T cell type 751VAIVQAVSAHRHRAR non-Hodgkin's lymphoma, peripheral T cell type 818VDKVLERDQKLSE lymph node, papillary carcinoma of thyroid, metastatic 819VDKVLERDQKLSELD lymph node, papillary carcinoma of thyroid, metastatic820 VDKVLERDQKLSELDD lymph node, papillary carcinoma of thyroid,metastatic 821 VDKVLERDQKLSELDDR lymph node, papillary carcinoma ofthyroid, metastatic 822 VLERDQKLSELDDR lymph node, papillary carcinomaof thyroid, metastatic 833 VDKVLERDQKLSE lymph node, papillary carcinomaof thyroid, metastatic 834 VDKVLERDQKLSELD lymph node, papillarycarcinoma of thyroid, metastatic 835 VDKVLERDQKLSELDD lymph node,papillary carcinoma of thyroid, metastatic 836 VDKVLERDQKLSELDDR lymphnode, papillary carcinoma of thyroid, metastatic 837 VLERDQKLSELDDRlymph node, papillary carcinoma of thyroid, metastatic 908DVGMFVALTKLGQPD uterine cervix, squamous cell carcinoma 909VGmFVALTKLGQPD uterine cervix, squamous cell carcinoma 218 GDYGRAFNLlymph node, non-Hodgkin's lymphoma, small lymphocytic type 219 TRHKIVHTKlymph node, non-Hodgkin's lymphoma, small lymphocytic type 221 KAFNWFSTLlymph node, non-Hodgkin's lymphoma, small lymphocytic type 541 RPKSNIVLnon-Hodgkin's lymphoma, diffuse large B-cell type 542 RPKSNIVLLnon-Hodgkin's lymphoma, diffuse large B-cell type 752 EEVITLIRSNQQLEpancreas, adenocarcinoma 753 EEVITLIRSNQQLEN pancreas, adenocarcinoma754 IPADTFAALKNPNAML pancreas, adenocarcinoma 755 LKQLLSDKQQKRQSGpancreas, adenocarcinoma 756 LKQLLSDKQQKRQSGQ pancreas, adenocarcinoma71 HLKSIPVSL prostate, adenocarcinoma 72 KVWYNVENW prostate,adenocarcinoma 73 LPAYRAQLL prostate, adenocarcinoma 74 LSEQTSVPLprostate, adenocarcinoma 75 SLNQWLVSF prostate, adenocarcinoma 76SMTSLAQKI prostate, adenocarcinoma 77 SSSGLHPPK prostate, adenocarcinoma527 DEKQQHIVY synovial sarcoma 528 DEVYQVTVY synovial sarcoma 529GEISEKAKL synovial sarcoma 530 YTMKEVLFY synovial sarcoma 165 ELNKLLEEIovary, adenocarcinoma, endometrioid type 166 IPFSNPRVL ovary,adenocarcinoma, endometrioid type 167 LLDEGAKLLY ovary, adenocarcinoma,endometrioid type 168 SPADAHRNL ovary, adenocarcinoma, endometrioid type96 APLQRSQSL kidney, renal cell carcinoma, clear cell type 97 DEVHQDTYkidney, renal cell carcinoma, clear cell type 98 LPHSATVTL kidney, renalcell carcinoma, clear cell type 278 ATNGDLASR prostate, benign nodularhyperplasia 279 GLHAEVTGVGY prostate, benign nodular hyperplasia 280HVSSTSSSF prostate, benign nodular hyperplasia 281 LQADLQNGL prostate,benign nodular hyperplasia 282 SELPVSEVA prostate, benign nodularhyperplasia 283 SQTKSVFEI prostate, benign nodular hyperplasia 284THIFTSDGL prostate, benign nodular hyperplasia 285 VIYFPPLQK prostate,benign nodular hyperplasia 286 YPFSSEQKW prostate, benign nodularhyperplasia 973 ADDLEGEAFLPL spleen, chronic myeloid leukemia 974ADDLEGEAFLPLR spleen, chronic myeloid leukemia 975 ADDLEGEAFLPLREspleen, chronic myeloid leukemia 976 GADDLEGEAFLPLR spleen, chronicmyeloid leukemia 141 AETTDNVFTL thyroid gland, follicular adenoma 142SEYQRFAVM thyroid gland, follicular adenoma 143 TFGERVVAF thyroid gland,follicular adenoma 144 NENLVERF colon, adenocarcinoma, mucinous type 845GIRVAPVPLYNS liver, hepatocellular carcinoma 846 GIRVAPVPLYNSFH liver,hepatocellular carcinoma 847 NPNGIRVAPVPLYNSFH liver, hepatocellularcarcinoma 478 AAVPVIISR lymph node, papillary carcinoma of thyroid,metastatic 479 EEIGKVAAA lymph node, papillary carcinoma of thyroid,metastatic 480 FLKDLVASV lymph node, papillary carcinoma of thyroid,metastatic 481 VIISRALEL lymph node, papillary carcinoma of thyroid,metastatic 420 QIDYKTLVL leiomyosarcoma 421 VEDPTIVRI leiomyosarcoma 543GEPLSYTRFSLARQ lung, non-small cell lung carcinoma, lung, adenocarcinoma544 GEPLSYTRFSLARQVD lung, non-small cell lung carcinoma, lung,adenocarcinoma 545 GEPLSYTRFSLARQVDG lung, non-small cell lungcarcinoma, lung, adenocarcinoma 546 GGEPLSYTRFSLARQVD lung, non-smallcell lung carcinoma, lung, adenocarcinoma 547 GGEPLSYTRFSLARQVDG lung,non-small cell lung carcinoma, lung, adenocarcinoma 548 NPGGYVAYSKAATVTGlung, non-small cell lung carcinoma, lung, adenocarcinoma 549NPGGYVAYSKAATVTGK lung, non-small cell lung carcinoma, lung,adenocarcinoma 550 NPGGYVAYSKAATVTGKL lung, non-small cell lungcarcinoma, lung, adenocarcinoma 551 NSVIIVDKNGRL lung, non-small celllung carcinoma, lung, adenocarcinoma 552 NSVIIVDKNGRLV lung, non-smallcell lung carcinoma, lung, adenocarcinoma 553 NSVIIVDKNGRLVY lung,non-small cell lung carcinoma, lung, adenocarcinoma 554 RVEYHFLSPYVSPKlung, non-small cell lung carcinoma, lung, adenocarcinoma 555RVEYHFLSPYVSPKE lung, non-small cell lung carcinoma, lung,adenocarcinoma 556 RVEYHFLSPYVSPKESPF lung, non-small cell lungcarcinoma, lung, adenocarcinoma 557 SPFRHVFWGSGSHTL lung, non-small celllung carcinoma, lung, adenocarcinoma 558 SVIIVDKNGRLV lung, non-smallcell lung carcinoma, lung, adenocarcinoma 559 VEYHFLSPYVSPK lung,non-small cell lung carcinoma, lung, adenocarcinoma 560 VEYHFLSPYVSPKElung, non-small cell lung carcinoma, lung, adenocarcinoma

B4GALT1 encodes a type II membrane-bound glycoprotein that appears tohave exclusive specificity for the donor substrate UDP-galactose(RefSeq). B4GALT1 was shown to be up-regulated in a variety of highlymetastatic cell lines such as human lung cancer and ovarian cancer celllines and was described as a valuable candidate biomarker of invasivephenotype of colorectal cancer (Poeta et al., 2012; Zhou et al., 2012).

CP encodes a metalloprotein that binds most of the copper in plasma andis involved in the peroxidation of Fe(II)transferrin to Fe(III)transferrin (RefSeq).

CST3 encodes a member of the cystatin superfamily, which encompassesproteins that contain multiple cystatin-like sequences (RefSeq).

CTSH encodes a lysosomal cysteine proteinase, which is important in theoverall degradation of lysosomal proteins (RefSeq). CTSH expression isincreased in pathologic conditions including breast carcinoma, melanoma,gliomas, colorectal carcinoma and prostate carcinoma. CTSH-mediatedprocessing of talin is thought to promote cancer cell progression byaffecting integrin activation and adhesion strength (Jevnikar et al.,2013).

DNAJC5 encodes a member of the J protein family. J proteins function inmany cellular processes by regulating the ATPase activity of 70 kDa heatshock proteins (RefSeq).

FAIM3 also known as TOSO encodes an Fc receptor for IgM (RefSeq). FAIM3was identified as being over-expressed and associated withanti-apoptotic characteristics in chronic lymphocytic leukemia and it isregulated by B-cell receptor activation. These studies show that FAIM3could be used as a prognostic marker for high-risk chronic lymphocyticleukemia (Pallasch et al., 2008; Yi et al., 2011; Yu et al., 2011).

FCER2 encodes a B-cell specific antigen and a low-affinity receptor forIgE. It has essential roles in B cell growth and differentiation, andthe regulation of IgE production (RefSeq).

FMOD encodes a member of the family of small interstitial proteoglycans.The encoded protein possesses a central region containing leucine-richrepeats with 4 keratan sulfate chains, flanked by terminal domainscontaining disulphide bonds (RefSeq). FMOD was shown to be highlyover-expressed in chronic lymphocytic leukemia cells. Hence, FMOD mightserve as potential tumor-associated antigen in chronic lymphocyticleukemia (Mayr et al., 2005).

GALNT1 encodes a member of theUDP-N-acetyl-alpha-D-galactosamine:polypeptideN-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes (RefSeq).Studies have revealed that GALNT1 expression correlates with the degreeof proliferation and recurrence in human breast cancer, ovarian cancerand bladder carcinoma. The latter suggests the use of GALNT1 as aclinical prognostic marker in human bladder carcinoma (Ding et al.,2012).

GLT8D1 encodes a member of the glycosyltransferase family (RefSeq).Studies revealed that GLT8D1 was ubiquitously up-regulated in themajority of human cancers, such as brain, liver, breast, lung, stomach,pancreas, colon, kidney, bladder, prostate and testis. GLT8D1-induceddifferentially methylated genes have strong potential as epigeneticbiomarkers for early cancer screening, diagnostic, prognostic andtherapeutic interventions (Teh et al., 2012).

GPI encodes a member of the glucose phosphate isomerase protein family(RefSeq). The GPI gene has been identified to be hypoxia inducible inhuman pancreatic cancer. The use of GPI inhibitors such aserythrose-4-phosphate diminishes the migratory and invasive capacitiesin bi-dimensional cultures of several breast cancer cell lines,suggesting that GPI inhibition could be a selective strategy to blocktumor metastasis (Yoon et al., 2001; Gallardo-Perez et al., 2014).

GPX1 encodes a member of the glutathione peroxidase family (RefSeq). TheGPX1 rs1050450 C>T polymorphism was associated with an increased risk ofbladder cancer, but not prostate cancer. High expression of GPX1 inbreast cancer cells of patients correlated with a worse clinical outcomeand reduced overall survival of patients who underwent chemotherapy,implying that GPX1 could be used as a prognostic marker for thesepatients (Jardim et al., 2013; Men et al., 2014).

TFRC encodes the transferrin receptor and it is located on chromosome3q29 (RefSeq). The expression rate of TFRC in oral squamous cellcarcinoma was significantly higher than that in dysplasia, suggestingthat oral squamous cell carcinoma disease progression might be relatedto TFRC expression. Anti-TFRC antibody blocked the interaction betweentransferrin and TFRC and, consequently, iron uptake. The resulting irondeprivation inhibited cell growth and induced apoptosis (Nagai et al.,2014).

UGCG encodes an enzyme that catalyzes the first glycosylation step inthe biosynthesis of glycosphingolipids, which are membrane componentscontaining lipid and sugar moieties (RefSeq). Studies have shown thatUGCG is over-expressed in leukemia, breast cancer, renal cell cancer andpapillary thyroid carcinomas. UGCG up-regulates MDR1 expression throughactivation of cSrc and beta-catenin signaling (Zhang et al., 2013; Liuet al., 2010).

The present invention furthermore relates to the peptides according tothe present invention that have the ability to bind to a molecule of thehuman major histocompatibility complex (MHC) class-I or -II.

The present invention further relates to the peptides according to thepresent invention wherein said peptides (each) consist or consistessentially of an amino acid sequence according to SEQ ID NO: 1 to SEQID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ IDNO: 1016.

A peptide consisting essentially of the amino acid sequence as indicatedcan have one or two non-anchor amino acids (see below regarding theanchor motif) exchanged without that the ability to bind to a moleculeof the human major histocompatibility complex (MHC) class-I or -II issubstantially changed or is negatively affected, compared to thenon-modified peptide. In another peptide consisting essentially of theamino acid sequence, one or two amino acids are exchanged with theirconservative exchange partners (see herein below as well) without thatthe ability to bind to a molecule of the human major histocompatibilitycomplex (MHC) class-I or -II is substantially changed or is negativelyaffected, compared to the non-modified peptide.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is modified and/or includesnon-peptide bonds.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is part of a fusion protein, inparticular fused to the N-terminal amino acids of the HLA-DRantigen-associated invariant chain (Ii), or fused to (or into thesequence of) an antibody, such as, for example, an antibody that isspecific for dendritic cells.

The present invention further relates to a nucleic acid, encoding thepeptides according to the present invention.

The present invention further relates to the nucleic acid according tothe present invention that is DNA, cDNA, PNA, RNA or combinationsthereof.

The present invention further relates to an expression vector capable ofexpressing and/or presenting a nucleic acid according to the presentinvention.

The present invention further relates to a peptide according to thepresent invention according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ IDNO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, anucleic acid according to the present invention or an expression vectoraccording to the present invention for use in medicine.

The present invention further relates to antibodies according to thepresent invention that are specific for a peptide according to SEQ IDNO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO:543 to SEQ ID NO: 1016, and methods of making them.

The present invention further relates to T-cell receptors (TCR), inparticular soluble TCR (sTCRs) targeting the peptides according to SEQID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ IDNO: 543 to SEQ ID NO: 1016 and/or complexes of said peptides accordingto the present invention with MHC, and methods of making them.

The present invention further relates to a host cell comprising anucleic acid according to the present invention or an expression vectoras described before.

The present invention further relates to the host cell according to thepresent invention that is an antigen presenting cell.

The present invention further relates to the host cell according to thepresent invention wherein the antigen presenting cell is a dendriticcell.

The present invention further relates to a method of producing a peptideaccording to the present invention, the method comprising culturing thehost cell according to the present invention, and isolating the peptidefrom the host cell or its culture medium.

The present invention further relates to an in vitro method forproducing activated cytotoxic T lymphocytes (CTL), the method comprisingcontacting in vitro CTL with antigen loaded human class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellfor a period of time sufficient to activate said CTL in an antigenspecific manner, wherein said antigen is any peptide according to thepresent invention.

The present invention further relates to the method according to thepresent invention, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellby contacting a sufficient amount of the antigen with anantigen-presenting cell.

The present invention further relates to the method according to thepresent invention, wherein the antigen-presenting cell comprises anexpression vector capable of expressing said peptide containing SEQ IDNO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO:552 to SEQ ID NO: 1016, or said variant amino acid sequence.

The present invention further relates to activated cytotoxic Tlymphocytes (CTL), produced by the method according to the presentinvention, which selectively recognize a cell which aberrantly expressesa polypeptide comprising an amino acid sequence according to the presentinvention.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the present invention,the method comprising administering to the patient an effective numberof cytotoxic T lymphocytes (CTL) as according to the present invention.

The present invention further relates to the use of any peptidedescribed, a nucleic acid according to the present invention, anexpression vector according to the present invention, a cell accordingto the present invention, or an activated cytotoxic T lymphocyteaccording to the present invention as a medicament or in the manufactureof a medicament.

The present invention further relates to a use according to the presentinvention, wherein said medicament is a vaccine.

The present invention further relates to a use according to the presentinvention, wherein the medicament is active against cancer.

The present invention further relates to a use according to the presentinvention, wherein said cancer cells are cells of haematologicalmalignancies, such as, CLL or AML cells.

The present invention further relates to particular marker proteins andbiomarkers based on the peptides according to the present invention thatcan be used in the diagnosis and/or prognosis of haematologicalmalignancies, in particular chronic lymphoid leukemia (CLL) cells.

Further, the present invention relates to the use of these novel targetsfor cancer treatment.

Further, the present invention relates to a method for producing apersonalized anti-cancer vaccine for an individual patient using adatabase (“warehouse”) of prescreened tumour associated peptides.

Stimulation of an immune response is dependent upon the presence ofantigens recognised as foreign by the host immune system. The discoveryof the existence of tumor associated antigens has raised the possibilityof using a host's immune system to intervene in tumor growth. Variousmechanisms of harnessing both the humoral and cellular arms of theimmune system are currently being explored for cancer immunotherapy.

Specific elements of the cellular immune response are capable ofspecifically recognising and destroying tumor cells. The isolation ofcytotoxic T-cells (CTL) from tumor-infiltrating cell populations or fromperipheral blood suggests that such cells play an important role innatural immune defences against cancer. CD8-positive T-cells inparticular, which recognise Class I molecules of the majorhistocompatibility complex (MHC)-bearing peptides of usually 8 to 10amino acid residues derived from proteins or defect ribosomal products(DRIPS) located in the cytosol, play an important role in this response.The MHC-molecules of the human are also designated as humanleukocyte-antigens (HLA).

There are two classes of MHC-molecules: MHC class I molecules that canbe found on most cells having a nucleus. MHC molecules are composed ofan alpha heavy chain and beta-2-microglobulin (MHC class I receptors) oran alpha and a beta chain (MHC class II receptors), respectively. Theirthree-dimensional conformation results in a binding groove, which isused for non-covalent interaction with peptides. MHC class I presentpeptides that result from proteolytic cleavage of predominantlyendogenous proteins, DRIPs and larger peptides. MHC class II moleculescan be found predominantly on professional antigen presenting cells(APCs), and primarily present peptides of exogenous or transmembraneproteins that are taken up by APCs during the course of endocytosis, andare subsequently processed. Complexes of peptide and MHC class Imolecules are recognized by CD8-positive cytotoxic T-lymphocytes bearingthe appropriate TCR (T-cell receptor), whereas complexes of peptide andMHC class II molecules are recognized by CD4-positive-helper-T cellsbearing the appropriate TCR. It is well known that the TCR, the peptideand the MHC are thereby present in a stoichiometric amount of 1:1:1.

CD4-positive helper T cells play an important role in inducing andsustaining effective responses by CD8-positive cytotoxic T cells. Theidentification of CD4-positive T-cell epitopes derived from tumorassociated antigens (TAA) is of great importance for the development ofpharmaceutical products for triggering anti-tumor immune responses(Gnjatic S, et al. Survey of naturally occurring CD4+ T cell responsesagainst NY-ESO-1 in cancer patients: correlation with antibodyresponses. Proc Natl Acad Sci USA. 2003 Jul. 22; 100(15):8862-7). At thetumor site, T helper cells, support a CTL friendly cytokine milieuMortara L, et al. CIITA-induced MHC class II expression in mammaryadenocarcinoma leads to a Th1 polarization of the tumormicroenvironment, tumor rejection, and specific antitumor memory. ClinCancer Res. 2006 Jun. 1; 12(11 Pt 1):3435-43) and attract effectorcells, e.g. CTLs, NK cells, macrophages, granulocytes (Hwang M L, et al.Cognate memory CD4+ T cells generated with dendritic cell priminginfluence the expansion, trafficking, and differentiation of secondaryCD8+ T cells and enhance tumor control. J Immunol. 2007 Nov. 1;179(9):5829-38).

In the absence of inflammation, expression of MHC class II molecules ismainly restricted to cells of the immune system, especially professionalantigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells,macrophages, dendritic cells. In cancer patients, cells of the tumorhave surprisingly been found to express MHC class II molecules (DengjelJ, et al. Unexpected abundance of HLA class II presented peptides inprimary renal cell carcinomas. Clin Cancer Res. 2006 Jul. 15; 12(14 Pt1):4163-70).

It was shown in mammalian animal models, e.g., mice, that even in theabsence of CTL effector cells (i.e., CD8-positive T lymphocytes),CD4-positive T cells are sufficient for inhibiting manifestation oftumors via inhibition of angiogenesis by secretion of interferon-gamma(IFNγ).

Additionally, it was shown that CD4-positive T cells recognizingpeptides from tumor-associated antigens presented by HLA class IImolecules can counteract tumor progression via the induction of antibody(Ab) responses.

In contrast to tumor-associated peptides binding to HLA class Imolecules, only a small number of class II ligands of tumor associatedantigens (TAA) have been described to date.

Since the constitutive expression of HLA class II molecules is usuallylimited to cells of the immune system, the possibility of isolatingclass II peptides directly from primary tumors was not consideredpossible. However, Dengjel et al. were successful in identifying anumber of MHC Class II epitopes directly from tumors (WO 2007/028574, EP1 760 088 B1; (Dengjel et al., 2006).

The antigens that are recognized by the tumor specific cytotoxic Tlymphocytes, that is, their epitopes, can be molecules derived from allprotein classes, such as enzymes, receptors, transcription factors, etc.which are expressed and, as compared to unaltered cells of the sameorigin, up-regulated in cells of the respective tumor.

Since both types of response, CD8 and CD4 dependent, contribute jointlyand synergistically to the anti-tumor effect, the identification andcharacterization of tumor-associated antigens recognized by either CD8+CTLs (ligand: MHC class I molecule+peptide epitope) or by CD4-positiveT-helper cells (ligand: MHC class II molecule+peptide epitope) isimportant in the development of tumor vaccines.

The present invention also relates to two new and very useful MHC classII peptides (according to SEQ ID NO: 543 to SEQ ID NO: 1016). Thesepeptides are particularly useful in the diagnosis and/or treatment ofCLL and other cancers over-expressing and/or over-presenting theantigens the peptides are derived from respectively, such as AML.

The present invention also relates to so-called length variants of theinventive MHC class II peptides according to SEQ ID NO: 543 to SEQ IDNO: 1016.

The length variants are generally N- and/or C-terminally extended(between 1 and 5, preferably 1 to 10 amino acids) or N- and/orC-terminally shortened (between 1 and 5 amino acids) peptides, whichstill can bind to MHC, and elicit a cellular immune response asdescribed herein. As is known in the state of the art, peptides bindingto class II proteins are not constrained in size and can vary from 11 to30 amino acids in length. The peptide binding groove in the MHC class IImolecules is open at both ends, which enables binding of peptides withrelatively longer length. Though the “core” nine residues long segmentcontributes the most to the recognition of the peptide, the flankingregions are also important for the specificity of the peptide to theclass II allele (see, for example, Meydan C, et al., Prediction ofpeptides binding to MHC class I and II alleles by temporal motif mining.BMC Bioinformatics. 2013; 14 Suppl 2: S13). Using the many softwaretools as available (e.g. as described above), the person of skill in theart will be able to identify the binding motif, and thus identify thepossibilities for extensions and/or deletions of the MHC class IIpeptides according to Table 1c, in order to create length variants.

For a peptide to trigger (elicit) a cellular immune response, it mustbind to an MHC-molecule. This process is dependent on the allele of theMHC-molecule and specific polymorphisms of the amino acid sequence ofthe peptide. MHC-class-1-binding peptides are usually 8-12 amino acidresidues in length and usually contain two conserved residues(“anchors”) in their sequence that interact with the correspondingbinding groove of the MHC-molecule. In this way each MHC allele has a“binding motif” determining which peptides can bind specifically to thebinding groove.

In the MHC class I dependent immune reaction, peptides not only have tobe able to bind to certain MHC class I molecules being expressed bytumor cells, they also have to be recognized by T cells bearing specificT cell receptors (TCR).

The antigens that are recognized by the tumor specific cytotoxic Tlymphocytes, that is, their epitopes, can be molecules derived from allprotein classes, such as enzymes, receptors, transcription factors, etc.which are expressed and, as compared to unaltered cells of the sameorigin, up-regulated in cells of the respective tumor.

The current classification of tumor associated antigens comprises thefollowing major groups:

a) Cancer-testis antigens: The first TAAs ever identified that can berecognized by T cells belong to this class, which was originally calledcancer-testis (CT) antigens because of the expression of its members inhistologically different human tumors and, among normal tissues, only inspermatocytes/spermatogonia of testis and, occasionally, in placenta.Since the cells of testis do not express class I and II HLA molecules,these antigens cannot be recognized by T cells in normal tissues and cantherefore be considered as immunologically tumor-specific. Well-knownexamples for CT antigens are the MAGE family members or NY-ESO-1.b) Differentiation antigens: These TAAs are shared between tumors andthe normal tissue from which the tumor arose; most are found inmelanomas and normal melanocytes. Many of these melanocytelineage-related proteins are involved in the biosynthesis of melanin andare therefore not tumor specific but nevertheless are widely used forcancer immunotherapy. Examples include, but are not limited to,tyrosinase and Melan-A/MART-1 for melanoma or PSA for prostate cancer.c) Overexpressed TAAs: Genes encoding widely expressed TAAs have beendetected in histologically different types of tumors as well as in manynormal tissues, generally with lower expression levels. It is possiblethat many of the epitopes processed and potentially presented by normaltissues are below the threshold level for T-cell recognition, whiletheir overexpression in tumor cells can trigger an anticancer responseby breaking previously established tolerance. Prominent examples forthis class of TAAs are Her-2/neu, Survivin, Telomerase or WT1.d) Tumor specific antigens: These unique TAAs arise from mutations ofnormal genes (such as β-catenin, CDK4, etc.). Some of these molecularchanges are associated with neoplastic transformation and/orprogression. Tumor specific antigens are generally able to induce strongimmune responses without bearing the risk for autoimmune reactionsagainst normal tissues. On the other hand, these TAAs are in most casesonly relevant to the exact tumor on which they were identified and areusually not shared between many individual tumors.e) TAAs arising from abnormal post-translational modifications: SuchTAAs may arise from proteins which are neither specific noroverexpressed in tumors but nevertheless become tumor associated byposttranslational processes primarily active in tumors. Examples forthis class arise from altered glycosylation patterns leading to novelepitopes in tumors as for MUC1 or events like protein splicing duringdegradation which may or may not be tumor specific.f) Oncoviral proteins: These TAAs are viral proteins that may play acritical role in the oncogenic process and, because they are foreign(not of human origin), they can evoke a T-cell response. Examples ofsuch proteins are the human papilloma type 16 virus proteins, E6 and E7,which are expressed in cervical carcinoma.

For proteins to be recognized by cytotoxic T-lymphocytes astumor-specific or -associated antigens, and to be used in a therapy,particular prerequisites must be fulfilled. The antigen should beexpressed mainly by tumor cells and not or in comparably small amountsby normal healthy tissues or in another preferred embodiment the peptideshould be over-presented by tumor cells as compared to normal healthytissues. It is furthermore desirable, that the respective antigen is notonly present in a type of tumor, but also in high concentrations (i.e.copy numbers of the respective peptide per cell). Tumor-specific andtumor-associated antigens are often derived from proteins directlyinvolved in transformation of a normal cell to a tumor cell due to afunction e.g. in cell cycle control or suppression of apoptosis.Additionally, downstream targets of the proteins directly causative fora transformation may be upregulated and thus may be indirectlytumor-associated. Such indirect tumor-associated antigens may also betargets of a vaccination approach (Singh-Jasuja et al., 2004). In bothcases it is essential that epitopes are present in the amino acidsequence of the antigen, since such a peptide (“immunogenic peptide”)that is derived from a tumor associated antigen should lead to an invitro or in vivo T-cell-response.

Basically, any peptide able to bind a MHC molecule may function as aT-cell epitope. A prerequisite for the induction of an in vitro or invivo T-cell-response is the presence of a T cell with a correspondingTCR and the absence of immunological tolerance for this particularepitope.

Therefore, TAAs are a starting point for the development of a tumorvaccine. The methods for identifying and characterizing the TAAs arebased on the use of CTL that can be isolated from patients or healthysubjects, or they are based on the generation of differentialtranscription profiles or differential peptide expression patternsbetween tumors and normal tissues.

However, the identification of genes over-expressed in tumor tissues orhuman tumor cell lines, or selectively expressed in such tissues or celllines, does not provide precise information as to the use of theantigens being transcribed from these genes in an immune therapy. Thisis because only an individual subpopulation of epitopes of theseantigens are suitable for such an application since a T cell with acorresponding TCR has to be present and immunological tolerance for thisparticular epitope needs to be absent or minimal. In a very preferredembodiment of the invention it is therefore important to select onlythose over- or selectively presented peptides against which a functionaland/or a proliferating T cell can be found. Such a functional T cell isdefined as a T cell, which upon stimulation with a specific antigen canbe clonally expanded and is able to execute effector functions(“effector T cell”).

In case of TCRs and antibodies according to the invention theimmunogenicity of the underlying peptides is secondary. For TCRs andantibodies according to the invention the presentation is thedetermining factor.

T-helper cells play an important role in orchestrating the effectorfunction of CTLs in anti-tumor immunity. T-helper cell epitopes thattrigger a T-helper cell response of the T_(H1) type support effectorfunctions of CD8-positive killer T cells, which include cytotoxicfunctions directed against tumor cells displaying tumor-associatedpeptide/MHC complexes on their cell surfaces. In this waytumor-associated T-helper cell peptide epitopes, alone or in combinationwith other tumor-associated peptides, can serve as active pharmaceuticalingredients of vaccine compositions that stimulate anti-tumor immuneresponses.

The inventors identified a novel category of ligandome-derivedtumor-associated antigens (LiTAAs), which were frequently andexclusively detected in CLL patients. Specific immune recognition of thecorresponding HLA ligands (LiTAPs) was observed exclusively in CLLpatients, remarkably showing a direct correlation with the frequency ofHLA restricted presentation. Furthermore, retrospective survivalanalysis of 33 CLL patients indicated a potential association ofLiTAP-specific immune responses with improved overall survival in CLLpatients.

Uses against further cancers are disclosed in the following descriptionof the proteins of the peptides according to the invention.

As used herein and except as noted otherwise all terms are defined asgiven below.

The term “peptide” is used herein to designate a series of amino acidresidues, connected one to the other typically by peptide bonds betweenthe alpha-amino and carbonyl groups of the adjacent amino acids. Thepeptides are preferably 9 amino acids in length, but can be as short as8 amino acids in length, and as long as 10, 11, 12, 13 or 14 and in caseof MHC class II peptides they can be as long as 15, 16, 17, 18, 19 or 20amino acids in length.

Furthermore, the term “peptide” shall include salts of a series of aminoacid residues, connected one to the other typically by peptide bondsbetween the alpha-amino and carbonyl groups of the adjacent amino acids.Preferably, the salts are pharmaceutical acceptable salts of thepeptides, such as, for example, the chloride or acetate(trifluoroacetate) salts.

The term “peptide” shall include “oligopeptide”. The term “oligopeptide”is used herein to designate a series of amino acid residues, connectedone to the other typically by peptide bonds between the alpha-amino andcarbonyl groups of the adjacent amino acids. The length of theoligopeptide is not critical to the invention, as long as the correctepitope or epitopes are maintained therein. The oligopeptides aretypically less than about 30 amino acid residues in length, and greaterthan about 15 amino acids in length.

The term “the peptides of the present invention” shall include thepeptides consisting of or comprising a peptide as defined aboveaccording to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ IDNO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016.

The term “polypeptide” designates a series of amino acid residues,connected one to the other typically by peptide bonds between thealpha-amino and carbonyl groups of the adjacent amino acids. The lengthof the polypeptide is not critical to the invention as long as thecorrect epitopes are maintained. In contrast to the terms peptide oroligopeptide, the term polypeptide is meant to refer to moleculescontaining more than about 30 amino acid residues.

A peptide, oligopeptide, protein or polynucleotide coding for such amolecule is “immunogenic” (and thus is an “immunogen” within the presentinvention), if it is capable of inducing an immune response. In the caseof the present invention, immunogenicity is more specifically defined asthe ability to induce a T-cell response. Thus, an “immunogen” would be amolecule that is capable of inducing an immune response, and in the caseof the present invention, a molecule capable of inducing a T-cellresponse. In another aspect, the immunogen can be the peptide, thecomplex of the peptide with MHC, oligopeptide, and/or protein that isused to raise specific antibodies or TCRs against it.

A class I T cell “epitope” requires a short peptide that is bound to aclass I MHC receptor, forming a ternary complex (MHC class I alphachain, beta-2-microglobulin, and peptide) that can be recognized by a Tcell bearing a matching T-cell receptor binding to the MHC/peptidecomplex with appropriate affinity. Peptides binding to MHC class Imolecules are typically 8-14 amino acids in length, and most typically 9amino acids in length.

In humans there are three different genetic loci that encode MHC class Imolecules (the MHC-molecules of the human are also designated humanleukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02,and HLA-B*07 are examples of different MHC class I alleles that can beexpressed from these loci.

Table 7: Expression frequencies F of HLA*A02 and the most frequentHLA-DR serotypes. Frequencies are deduced from haplotype frequenciesG_(f) within the American population adapted from Mori et al. (Mori M,et al. HLA gene and haplotype frequencies in the North Americanpopulation: the National Marrow Donor Program Donor Registry.Transplantation. 1997 Oct. 15; 64(7):1017-27) employing theHardy-Weinberg formula F=1−(1−G_(f))². Combinations of A*02 with certainHLA-DR alleles might be enriched or less frequent than expected fromtheir single frequencies due to linkage disequilibrium. For detailsrefer to Chanock et al. (S. J. Chanock, et al (2004) HLA-A, —B, -Cw,-DQA1 and DRB1 in an African American population from Bethesda, USAHuman Immunology, 65: 1223-1235).

Expression frequencies of HLA*02 and HLA-DR serotypes within NorthAmerican subpopulations HLA Caucasian African Asian Latin AlleleAmerican American American American A*02 49.1% 34.1% 43.2% 48.3% DR119.4% 13.2% 6.8% 15.3% DR2 28.2% 29.8% 33.8% 21.2% DR3 20.6% 24.8% 9.2%15.2% DR4 30.7% 11.1% 28.6% 36.8% DR5 23.3% 31.1% 30.0% 20.0% DR6 26.7%33.7% 25.1% 31.1% DR7 24.8% 19.2% 13.4% 20.2% DR8 5.7% 12.1% 12.7% 18.6%DR9 2.1% 5.8% 18.6% 2.1%

Therefore, for therapeutic and diagnostic purposes a peptide that bindswith appropriate affinity to several different HLA class II receptors ishighly desirable. A peptide binding to several different HLA class IImolecules is called a promiscuous binder.

As used herein, reference to a DNA sequence includes both singlestranded and double stranded DNA. Thus, the specific sequence, unlessthe context indicates otherwise, refers to the single strand DNA of suchsequence, the duplex of such sequence with its complement (doublestranded DNA) and the complement of such sequence. The term “codingregion” refers to that portion of a gene which either naturally ornormally codes for the expression product of that gene in its naturalgenomic environment, i.e., the region coding in vivo for the nativeexpression product of the gene.

The coding region can be from a non-mutated (“normal”), mutated oraltered gene, or can even be from a DNA sequence, or gene, whollysynthesized in the laboratory using methods well known to those of skillin the art of DNA synthesis.

The term “nucleotide sequence” refers to a heteropolymer ofdeoxyribonucleotides.

The nucleotide sequence coding for a particular peptide, oligopeptide,or polypeptide may be naturally occurring or they may be syntheticallyconstructed. Generally, DNA segments encoding the peptides,polypeptides, and proteins of this invention are assembled from cDNAfragments and short oligonucleotide linkers, or from a series ofoligonucleotides, to provide a synthetic gene that is capable of beingexpressed in a recombinant transcriptional unit comprising regulatoryelements derived from a microbial or viral operon.

As used herein the term “a nucleotide coding (or encoding) for apeptide” refers to a nucleotide sequence coding for the peptideincluding artificial (man-made) start and stop codons compatible for thebiological system the sequence is going to be expressed by.

The term “expression product” means the polypeptide or protein that isthe natural translation product of the gene and any nucleic acidsequence coding equivalents resulting from genetic code degeneracy andthus coding for the same amino acid(s).

The term “fragment”, when referring to a coding sequence, means aportion of DNA comprising less than the complete coding region, whoseexpression product retains essentially the same biological function oractivity as the expression product of the complete coding region.

The term “DNA segment” refers to a DNA polymer, in the form of aseparate fragment or as a component of a larger DNA construct, which hasbeen derived from DNA isolated at least once in substantially pure form,i.e., free of contaminating endogenous materials and in a quantity orconcentration enabling identification, manipulation, and recovery of thesegment and its component nucleotide sequences by standard biochemicalmethods, for example, by using a cloning vector. Such segments areprovided in the form of an open reading frame uninterrupted by internalnon-translated sequences, or introns, which are typically present ineukaryotic genes. Sequences of non-translated DNA may be presentdownstream from the open reading frame, where the same do not interferewith manipulation or expression of the coding regions.

The term “primer” means a short nucleic acid sequence that can be pairedwith one strand of DNA and provides a free 3′-OH end at which a DNApolymerase starts synthesis of a deoxyribonucleotide chain.

The term “promoter” means a region of DNA involved in binding of RNApolymerase to initiate transcription.

The term “isolated” means that the material is removed from its originalenvironment (e.g., the natural environment if it is naturallyoccurring). For example, a naturally-occurring polynucleotide orpolypeptide present in a living animal is not isolated, but the samepolynucleotide or polypeptide, separated from some or all of thecoexisting materials in the natural system, is isolated. Suchpolynucleotides could be part of a vector and/or such polynucleotides orpolypeptides could be part of a composition, and still be isolated inthat such vector or composition is not part of its natural environment.

The polynucleotides, and recombinant or immunogenic polypeptides,disclosed in accordance with the present invention may also be in“purified” form. The term “purified” does not require absolute purity;rather, it is intended as a relative definition, and can includepreparations that are highly purified or preparations that are onlypartially purified, as those terms are understood by those of skill inthe relevant art. For example, individual clones isolated from a cDNAlibrary have been conventionally purified to electrophoretichomogeneity. Purification of starting material or natural material to atleast one order of magnitude, preferably two or three orders, and morepreferably four or five orders of magnitude is expressly contemplated.Furthermore, a claimed polypeptide which has a purity of preferably99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weightor greater is expressly contemplated.

The nucleic acids and polypeptide expression products disclosedaccording to the present invention, as well as expression vectorscontaining such nucleic acids and/or such polypeptides, may be in“enriched form”. As used herein, the term “enriched” means that theconcentration of the material is at least about 2, 5, 10, 100, or 1000times its natural concentration (for example), advantageously 0.01%, byweight, preferably at least about 0.1% by weight. Enriched preparationsof about 0.5%, 1%, 5%, 10%, and 20% by weight are also contemplated. Thesequences, constructs, vectors, clones, and other materials comprisingthe present invention can advantageously be in enriched or isolatedform.

The term “active fragment” means a fragment that generates an immuneresponse (i.e., has immunogenic activity) when administered, alone oroptionally with a suitable adjuvant, to an animal, such as a mammal, forexample, a rabbit or a mouse, and also including a human, such immuneresponse taking the form of stimulating a T-cell response within therecipient animal, such as a human. Alternatively, the “active fragment”may also be used to induce a T-cell response in vitro.

As used herein, the terms “portion”, “segment” and “fragment,” when usedin relation to polypeptides, refer to a continuous sequence of residues,such as amino acid residues, which sequence forms a subset of a largersequence. For example, if a polypeptide were subjected to treatment withany of the common endopeptidases, such as trypsin or chymotrypsin, theoligopeptides resulting from such treatment would represent portions,segments or fragments of the starting polypeptide. When used in relationto polynucleotides, these terms refer to the products produced bytreatment of said polynucleotides with any of the endonucleases.

In accordance with the present invention, the term “percent identity” or“percent identical”, when referring to a sequence, means that a sequenceis compared to a claimed or described sequence after alignment of thesequence to be compared (the “Compared Sequence”) with the described orclaimed sequence (the “Reference Sequence”). The Percent Identity isthen determined according to the following formula:Percent Identity=100[1−(C/R)]wherein C is the number of differences between the Reference Sequenceand the Compared Sequence over the length of alignment between theReference Sequence and the Compared Sequence, wherein(i) each base or amino acid in the Reference Sequence that does not havea corresponding aligned base or amino acid in the Compared Sequence and(ii) each gap in the Reference Sequence and(iii) each aligned base or amino acid in the Reference Sequence that isdifferent from an aligned base or amino acid in the Compared Sequence,constitutes a difference and(iiii) the alignment has to start at position 1 of the alignedsequences;and R is the number of bases or amino acids in the Reference Sequenceover the length of the alignment with the Compared Sequence with any gapcreated in the Reference Sequence also being counted as a base or aminoacid.

If an alignment exists between the Compared Sequence and the ReferenceSequence for which the Percent Identity as calculated above is aboutequal to or greater than a specified minimum Percent Identity then theCompared Sequence has the specified minimum Percent Identity to theReference Sequence even though alignments may exist in which the hereinabove calculated Percent Identity is less than the specified PercentIdentity.

The original (unmodified) peptides as disclosed herein can be modifiedby the substitution of one or more residues at different, possiblyselective, sites within the peptide chain, if not otherwise stated.Preferably those substitutions are located at the end of the amino acidchain. Such substitutions may be of a conservative nature, for example,where one amino acid is replaced by an amino acid of similar structureand characteristics, such as where a hydrophobic amino acid is replacedby another hydrophobic amino acid. Even more conservative would bereplacement of amino acids of the same or similar size and chemicalnature, such as where leucine is replaced by isoleucine. In studies ofsequence variations in families of naturally occurring homologousproteins, certain amino acid substitutions are more often tolerated thanothers, and these are often show correlation with similarities in size,charge, polarity, and hydrophobicity between the original amino acid andits replacement, and such is the basis for defining “conservativesubstitutions.”

Conservative substitutions are herein defined as exchanges within one ofthe following five groups: Group 1-small aliphatic, nonpolar or slightlypolar residues (Ala, Ser, Thr, Pro, Gly); Group 2-polar, negativelycharged residues and their amides (Asp, Asn, Glu, Gln); Group 3-polar,positively charged residues (His, Arg, Lys); Group 4-large, aliphatic,nonpolar residues (Met, Leu, Ile, Val, Cys); and Group 5-large, aromaticresidues (Phe, Tyr, Trp).

Less conservative substitutions might involve the replacement of oneamino acid by another that has similar characteristics but is somewhatdifferent in size, such as replacement of an alanine by an isoleucineresidue. Highly non-conservative replacements might involve substitutingan acidic amino acid for one that is polar, or even for one that isbasic in character. Such “radical” substitutions cannot, however, bedismissed as potentially ineffective since chemical effects are nottotally predictable and radical substitutions might well give rise toserendipitous effects not otherwise predictable from simple chemicalprinciples.

Of course, such substitutions may involve structures other than thecommon L-amino acids. Thus, D-amino acids might be substituted for theL-amino acids commonly found in the antigenic peptides of the inventionand yet still be encompassed by the disclosure herein. In addition,amino acids possessing non-standard R groups (i.e., R groups other thanthose found in the common 20 amino acids of natural proteins) may alsobe used for substitution purposes to produce immunogens and immunogenicpolypeptides according to the present invention.

If substitutions at more than one position are found to result in apeptide with substantially equivalent or greater antigenic activity asdefined below, then combinations of those substitutions will be testedto determine if the combined substitutions result in additive orsynergistic effects on the antigenicity of the peptide. At most, no morethan 4 positions within the peptide would simultaneously be substituted.

The peptides of the invention can be elongated by up to four aminoacids, that is 1, 2, 3 or 4 amino acids can be added to either end inany combination between 4:0 and 0:4.

Combinations of the elongations according to the invention can bedepicted from table 8:

C-terminus N-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0 or 1 or 2 or 3 0 0or 1 or 2 or 3 or 4 N-terminus C-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0or 1 or 2 or 3 0 0 or 1 or 2 or 3 or 4

The amino acids for the elongation can be the peptides of the originalsequence of the protein or any other amino acid. The elongation can beused to enhance the stability or solubility of the peptides.

The term “T-cell response” means the specific proliferation andactivation of effector functions induced by a peptide in vitro or invivo. For MHC class I restricted CTLs, effector functions may be lysisof peptide-pulsed, peptide-precursor pulsed or naturallypeptide-presenting target cells, secretion of cytokines, preferablyInterferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion ofeffector molecules, preferably granzymes or perforins induced bypeptide, or degranulation.

Preferably, when the CTLs specific for a peptide according to thepresent invention are tested against the substituted peptides, thepeptide concentration at which the substituted peptides achieve half themaximal increase in lysis relative to background is no more than about 1mM, preferably no more than about 1 μM, more preferably no more thanabout 1 nM, and still more preferably no more than about 100 pM, andmost preferably no more than about 10 pM. It is also preferred that thesubstituted peptide be recognized by CTLs from more than one individual,at least two, and more preferably three individuals.

Thus, the epitopes of the present invention may be identical tonaturally occurring tumor-associated or tumor-specific epitopes or mayinclude epitopes that differ by no more than 4 residues from thereference peptide, as long as they have substantially identicalantigenic activity.

Stimulation of an immune response is dependent upon the presence ofantigens recognized as foreign by the host immune system. The discoveryof the existence of tumor associated antigens has now raised thepossibility of using a host's immune system to intervene in tumorgrowth. Various mechanisms of harnessing both the humoral and cellulararms of the immune system are currently explored for cancerimmunotherapy.

Specific elements of the cellular immune response are capable ofspecifically recognizing and destroying tumor cells. The isolation ofcytotoxic T-cells (CTL) from tumor-infiltrating cell populations or fromperipheral blood suggests that such cells play an important role innatural immune defences against cancer. CD8-positive T-cells inparticular, which recognize class I molecules of the majorhistocompatibility complex (MHC)-bearing peptides of usually 8 to 12residues derived from proteins or defect ribosomal products (DRIPS)located in the cytosols, play an important role in this response. TheMHC-molecules of the human are also designated as humanleukocyte-antigens (HLA).

MHC class I molecules can be found on most cells having a nucleus whichpresent peptides that result from proteolytic cleavage of mainlyendogenous, cytosolic or nuclear proteins, DRIPS, and larger peptides.However, peptides derived from endosomal compartments or exogenoussources are also frequently found on MHC class I molecules. Thisnon-classical way of class I presentation is referred to ascross-presentation in literature.

Since both types of response, CD8 and CD4 dependent, contribute jointlyand synergistically to the anti-tumor effect, the identification andcharacterization of tumor-associated antigens recognized by eitherCD8-positive CTLs (MHC class I molecule) or by CD4-positive CTLs (MHCclass II molecule) is important in the development of tumor vaccines. Itis therefore an object of the present invention, to provide compositionsof peptides that contain peptides binding to MHC complexes of eitherclass.

Considering the severe side-effects and expense associated with treatingcancer better prognosis and diagnostic methods are desperately needed.Therefore, there is a need to identify other factors representingbiomarkers for cancer in general and CLL in particular. Furthermore,there is a need to identify factors that can be used in the treatment ofcancer in general and CLL in particular.

The present invention provides peptides that are useful in treatingcancers/tumors, preferably CLL that over- or exclusively present thepeptides of the invention. These peptides were shown by massspectrometry to be naturally presented by HLA molecules on primary humanCLL samples.

The source gene/protein (also designated “full-length protein” or“underlying protein”) from which the peptides are derived were shown tobe highly overexpressed in diseased (e.g. cancerous) compared withnormal tissues. “Normal tissues” in relation to this invention shallparticularly mean a blood sample from a healthy donor andsub-populations of blood cells, especially white blood cells, (seeexample 2, and FIGS. 2a-2f ) demonstrating a high degree of tumorassociation of the source genes. Moreover, the peptides themselves arestrongly over-presented on tumor tissue—“tumor tissue” in relation tothis invention shall mean a blood sample from a patient suffering fromCLL and sub-populations of blood cells, especially white blood cells,but not on normal tissues (see example 3 and FIGS. 3a-3e ).

HLA-bound peptides can be recognized by the immune system, specificallyT lymphocytes/T cells. T cells can destroy the cells presenting therecognized HLA/peptide complex, e.g. cells presenting the peptides ofthe present invention that are derived from their underlying proteins.

The peptides of the present invention have been shown to be capable ofstimulating T cell responses and/or are over-presented and thus can beused for the production of antibodies and/or TCRs, in particular sTCRs,according to the present invention (see example 4 and FIG. 4a-4g ).Furthermore, the peptides when complexed with the respective MHC can beused for the production of antibodies and/or TCRs, in particular sTCRs,according to the present invention, as well. Respective methods are wellknown to the person of skill, and can be found in the respectiveliterature as well. Thus, the peptides of the present invention areuseful for generating an immune response in a patient by which tumorcells can be destroyed. An immune response in a patient can be inducedby direct administration of the described peptides or suitable precursorsubstances (e.g. elongated peptides, proteins, or nucleic acids encodingthese peptides) to the patient, ideally in combination with an agentenhancing the immunogenicity (i.e. an adjuvant). The immune responseoriginating from such a therapeutic vaccination can be expected to behighly specific against tumor cells because the target peptides of thepresent invention are not presented on normal tissues in comparable copynumbers, preventing the risk of undesired autoimmune reactions againstnormal cells in the patient.

A “pharmaceutical composition” is a composition suitable foradministration to a human being in a medical setting. Preferably, saidpharmaceutical composition is sterile and produced according to the GMPguidelines.

The pharmaceutical compositions comprise the peptides either in the freeform or in the form of a pharmaceutically acceptable salt (see alsoabove). As used herein, “a pharmaceutically acceptable salt” refers to aderivative of the disclosed peptides wherein the peptide is modified bymaking acid or base salts of the agent. For example, acid salts areprepared from the free base (typically wherein the neutral form of thedrug has a neutral —NH₂ group) involving reaction with a suitable acid.Suitable acids for preparing acid salts include both organic acids,e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonicacid, salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acidphosphoric acid and the like. Conversely, preparation of basic salts ofacid moieties which may be present on a peptide are prepared using apharmaceutically acceptable base such as sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or thelike.

In an especially preferred embodiment, the pharmaceutical compositionscomprise the peptides as salts of acetic acid (acetates), trifluoroacetates or hydrochloric acid (chlorides).

In addition to being useful for treating cancer, the peptides of thepresent invention are also useful as diagnostics. Since the peptideswere generated from CLL (leukemia) cells and since it was determinedthat these peptides are not or at lower levels present in normal tissues(such as white blood cells), these peptides can be used to diagnose thepresence of a cancer.

The presence of claimed peptides in blood samples can assist apathologist in diagnosis of cancer. Detection of certain peptides bymeans of antibodies, mass spectrometry or other methods known in the artcan tell the pathologist that the sample is malignant or generallydiseased, or can be used as a biomarker for CLL. Presence of groups ofpeptides can enable classification or sub-classification of diseasedtissues.

The detection of peptides on diseased tissue specimen can enable thedecision about the benefit of therapies involving the immune system,especially if T-lymphocytes are known or expected to be involved in themechanism of action. Loss of MHC expression is a well describedmechanism by which infected of malignant cells escapeimmuno-surveillance. Thus, presence of peptides shows that thismechanism is not exploited by the analyzed cells.

The peptides of the present invention might be used to analyzelymphocyte responses against those peptides such as T cell responses orantibody responses against the peptide or the peptide complexed to MHCmolecules. These lymphocyte responses can be used as prognostic markersfor decision on further therapy steps. These responses can also be usedas surrogate markers in immunotherapy approaches aiming to inducelymphocyte responses by different means, e.g. vaccination of protein,nucleic acids, autologous materials, adoptive transfer of lymphocytes.In gene therapy settings, lymphocyte responses against peptides can beconsidered in the assessment of side effects. Monitoring of lymphocyteresponses might also be a valuable tool for follow-up examinations oftransplantation therapies, e.g. for the detection of graft versus hostand host versus graft diseases.

The peptides of the present invention can be used to generate anddevelop specific antibodies against MHC/peptide complexes. These can beused for therapy, targeting toxins or radioactive substances to thediseased tissue. Another use of these antibodies can be targetingradionuclides to the diseased tissue for imaging purposes such as PET.This use can help to detect small metastases or to determine the sizeand precise localization of diseased tissues.

Therefore, it is a further aspect of the invention to provide a methodfor producing a recombinant antibody specifically binding to a humanmajor histocompatibility complex (MHC) class I or II being complexedwith a HLA-restricted antigen, the method comprising: immunizing agenetically engineered non-human mammal comprising cells expressing saidhuman major histocompatibility complex (MHC) class I or II with asoluble form of a MHC class I or II molecule being complexed with saidHLA-restricted antigen; isolating mRNA molecules from antibody producingcells of said non-human mammal; producing a phage display librarydisplaying protein molecules encoded by said mRNA molecules; andisolating at least one phage from said phage display library, said atleast one phage displaying said antibody specifically binding to saidhuman major histocompatibility complex (MHC) class I or II beingcomplexed with said HLA-restricted antigen.

It is a further aspect of the invention to provide an antibody thatspecifically binds to a human major histocompatibility complex (MHC)class I or II being complexed with a HLA-restricted antigen, wherein theantibody preferably is a polyclonal antibody, monoclonal antibody,bi-specific antibody and/or a chimeric antibody.

Yet another aspect of the present invention then relates to a method ofproducing said antibody specifically binding to a human majorhistocompatibility complex (MHC) class I or II being complexed with aHLA-restricted antigen, the method comprising: immunizing a geneticallyengineered non-human mammal comprising cells expressing said human majorhistocompatibility complex (MHC) class I or II with a soluble form of aMHC class I or II molecule being complexed with said HLA-restrictedantigen; isolating mRNA molecules from antibody producing cells of saidnon-human mammal; producing a phage display library displaying proteinmolecules encoded by said mRNA molecules; and isolating at least onephage from said phage display library, said at least one phagedisplaying said antibody specifically bindable to said human majorhistocompatibility complex (MHC) class I or II being complexed with saidHLA-restricted antigen. Respective methods for producing such antibodiesand single chain class I major histocompatibility complexes, as well asother tools for the production of these antibodies are disclosed in WO03/068201, WO 2004/084798, WO 01/72768, WO 03/070752, and Cohen C J, etal. Recombinant antibodies with MHC-restricted, peptide-specific, T-cellreceptor-like specificity: new tools to study antigen presentation andTCR-peptide-MHC interactions. J Mol Recognit. 2003 September-October;16(5):324-32; Denkberg G, et al. Selective targeting of melanoma andAPCs using a recombinant antibody with TCR-like specificity directedtoward a melanoma differentiation antigen. J Immunol. 2003 Sep. 1;171(5):2197-207; and Cohen C J, et al. Direct phenotypic analysis ofhuman MHC class I antigen presentation: visualization, quantitation, andin situ detection of human viral epitopes using peptide-specific,MHC-restricted human recombinant antibodies. J Immunol. 2003 Apr. 15;170(8):4349-61, which for the purposes of the present invention are allexplicitly incorporated by reference in their entireties.

Preferably, the antibody is binding with a binding affinity of below 20nanomolar, preferably of below 10 nanomolar, to the complex, which isregarded as “specific” in the context of the present invention.

It is a further aspect of the invention to provide a method forproducing a soluble T-cell receptor recognizing a specific peptide-MHCcomplex. Such soluble T-cell receptors can be generated from specificT-cell clones, and their affinity can be increased by mutagenesistargeting the complementarity-determining regions. For the purpose ofT-cell receptor selection, phage display can be used (US 2010/0113300,Liddy N, et al. Monoclonal TCR-redirected tumor cell killing. Nat Med2012 June; 18(6):980-987). For the purpose of stabilization of T-cellreceptors during phage display and in case of practical use as drug,alpha and beta chain can be linked e.g. by non-native disulfide bonds,other covalent bonds (single-chain T-cell receptor), or by dimerizationdomains (see Boulter J M, et al. Stable, soluble T-cell receptormolecules for crystallization and therapeutics. Protein Eng 2003September; 16(9):707-711; Card K F, et al. A soluble single-chain T-cellreceptor IL-2 fusion protein retains MHC-restricted peptide specificityand IL-2 bioactivity. Cancer Immunol Immunother 2004 April;53(4):345-357; and Willcox B E, et al. Production of soluble alphabetaT-cell receptor heterodimers suitable for biophysical analysis of ligandbinding. Protein Sci 1999 November; 8 (11):2418-2423). The T-cellreceptor can be linked to toxins, drugs, cytokines (see US2013/0115191), domains recruiting effector cells such as an anti-CD3domain, etc., in order to execute particular functions on target cells.Moreover, it could be expressed in T cells used for adoptive transfer.

Further information can be found in WO 2004/033685A1 and WO2004/074322A1. A combination of sTCRs is described in WO 2012/056407A1.Further methods for the production are disclosed in WO 2013/057586A1.

In addition, they can be used to verify a pathologist's diagnosis of acancer based on a biopsied sample.

In order to select over-presented peptides, a presentation profile iscalculated showing the median sample presentation as well as replicatevariation. The profile juxtaposes samples of the tumor entity ofinterest to a baseline of normal tissue samples. Each of these profilescan then be consolidated into an over-presentation score by calculatingthe p-value of a Linear Mixed-Effects Model (J. Pinheiro, et al. Thenlme Package: Linear and Nonlinear Mixed Effects Models. 2007) adjustingfor multiple testing by False Discovery Rate (Y. Benjamini and Y.Hochberg. Controlling the False Discovery Rate: A Practical and PowerfulApproach to Multiple Testing. Journal of the Royal Statistical Society.Series B (Methodological), Vol. 57 (No. 1):289-300, 1995).

For the identification and relative quantitation of HLA ligands by massspectrometry, HLA molecules from shock-frozen tissue samples werepurified and HLA-associated peptides were isolated. The isolatedpeptides were separated and sequences were identified by onlinenano-electrospray-ionization (nanoESI) liquid chromatography-massspectrometry (LC-MS) experiments. The resulting peptide sequences wereverified by comparison of the fragmentation pattern of natural TUMAPsrecorded from CLL samples with the fragmentation patterns ofcorresponding synthetic reference peptides of identical sequences. Sincethe peptides were directly identified as ligands of HLA molecules ofprimary tumors, these results provide direct evidence for the naturalprocessing and presentation of the identified peptides on primary cancertissue obtained from CLL patients.

The discovery pipeline XPRESIDENT® v2.1 (see, for example, US2013-0096016, which is hereby incorporated by reference in its entirety)allows the identification and selection of relevant over-presentedpeptide vaccine candidates based on direct relative quantitation ofHLA-restricted peptide levels on cancer tissues in comparison to severaldifferent non-cancerous tissues and organs. This was achieved by thedevelopment of label-free differential quantitation using the acquiredLC-MS data processed by a proprietary data analysis pipeline, combiningalgorithms for sequence identification, spectral clustering, ioncounting, retention time alignment, charge state deconvolution andnormalization.

Presentation levels including error estimates for each peptide andsample were established. Peptides exclusively presented on tumor tissueand peptides over-presented in tumor versus non-cancerous tissues andorgans have been identified.

HLA-peptide complexes from CLL tissue samples were purified andHLA-associated peptides were isolated and analysed by LC-MS (seeexamples). All TUMAPs contained in the present application wereidentified with this approach on primary CLL samples confirming theirpresentation on primary CLL.

All TUMAPs contained in the application at hand were identified withthis approach on primary CLL samples confirming their presentation onprimary CLL.

TUMAPs identified on multiple CLL tumor and normal tissues werequantified using ion-counting of label-free LC-MS data. The methodassumes that LC-MS signal areas of a peptide correlate with itsabundance in the sample. All quantitative signals of a peptide invarious LC-MS experiments were normalized based on central tendency,averaged per sample and merged into a bar plot, called presentationprofile. The presentation profile consolidates different analysismethods like protein database search, spectral clustering, charge statedeconvolution (decharging) and retention time alignment andnormalization.

The present invention therefore relates to a peptide comprising asequence that is selected from the group consisting of SEQ ID NO: 1 toSEQ ID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 toSEQ ID NO: 1016 or a variant thereof which is at least 90% homologous(preferably identical) to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016 or a variantthereof that induces T cells cross-reacting with said peptide, whereinsaid peptide is not the underlying full-length polypeptide.

The present invention further relates to a peptide comprising a sequencethat is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO:225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ ID NO:1024 or a variant thereof which is at least 90% homologous (preferablyidentical) to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 527 to SEQ IDNO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016, wherein said peptide orvariant has an overall length of between 8 and 100, preferably between 8and 30, and most preferred between 8 and 14 amino acids.

The present invention further relates to the peptides according to theinvention that have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class-I or -II.

The present invention further relates to the peptides according to theinvention wherein the peptide consists or consists essentially of anamino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 225, SEQ IDNO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ ID NO: 1016.

The present invention further relates to the peptides according to theinvention, wherein the peptide is (chemically) modified and/or includesnon-peptide bonds.

The present invention further relates to the peptides according to theinvention, wherein the peptide is part of a fusion protein, inparticular comprising N-terminal amino acids of the HLA-DRantigen-associated invariant chain (Ii), or wherein the peptide is fusedto (or into) an antibody, such as, for example, an antibody that isspecific for dendritic cells.

The present invention further relates to a nucleic acid, encoding thepeptides according to the invention, provided that the peptide is notthe full human protein.

The present invention further relates to the nucleic acid according tothe invention that is DNA, cDNA, PNA, RNA or combinations thereof.

The present invention further relates to an expression vector capable ofexpressing a nucleic acid according to the invention.

The present invention further relates to a peptide according to theinvention, a nucleic acid according to the invention or an expressionvector according to the invention for use in medicine.

The present invention further relates to a host cell comprising anucleic acid according to the invention or an expression vectoraccording to the invention.

The present invention further relates to the host cell according to theinvention that is an antigen presenting cell.

The present invention further relates to the host cell according to theinvention wherein the antigen presenting cell is a dendritic cell.

The present invention further relates to a method for producing apeptide according to the invention, the method comprising culturing thehost cell described, and isolating the peptide from the host cell or itsculture medium.

The present invention further relates to an in vitro method forproducing activated cytotoxic T lymphocytes (CTL), the method comprisingcontacting in vitro CTL with antigen loaded human class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellfor a period of time sufficient to activate said CTL in an antigenspecific manner, wherein said antigen is any peptide according to theinvention.

The present invention further relates to the method as described,wherein said antigen is loaded onto class I or II MHC moleculesexpressed on the surface of a suitable antigen-presenting cell bycontacting a sufficient amount of the antigen with an antigen-presentingcell.

The present invention further relates to the method according to theinvention, wherein the antigen-presenting cell comprises an expressionvector capable of expressing said peptide containing SEQ ID NO: 1 to SEQID NO: 225, SEQ ID NO: 527 to SEQ ID NO: 551 or SEQ ID NO: 552 to SEQ IDNO: 1016 or said variant amino acid sequence.

The present invention further relates to activated cytotoxic Tlymphocytes (CTL), produced by the method according to the invention,which selectively recognise a cell which aberrantly expresses apolypeptide comprising an amino acid sequence described.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the invention, themethod comprising administering to the patient an effective number ofcytotoxic T lymphocytes (CTL) according to the invention.

The present invention further relates to the use of any peptideaccording to the invention, a nucleic acid according to the invention,an expression vector according to the invention, a cell according to theinvention, or an activated cytotoxic T lymphocyte according to theinvention as a medicament or in the manufacture of a medicament.

The present invention further relates to a use according to theinvention, wherein the medicament is a vaccine.

The present invention further relates to a use according to theinvention, wherein the medicament is active against cancer.

The present invention further relates to a use according to theinvention, wherein said cancer cells are CLL cells or other non solidtumor cells.

The present invention further relates to particular marker proteins andbiomarkers that can be used in the prognosis of CLL.

Further, the present invention relates to the use of the novel targetsas described in accordance with the present invention for cancertreatment.

The term “antibody” or “antibodies” is used herein in a broad sense andincludes both polyclonal and monoclonal antibodies. In addition tointact or “full” immunoglobulin molecules, also included in the term“antibodies” are fragments or polymers of those immunoglobulin moleculesand humanized versions of immunoglobulin molecules, so long as theyexhibit any of the desired properties (e.g., specific binding of an CLLmarker polypeptide, delivery of a toxin to an CLL (leukemia) cellsexpressing a CLL marker gene at an increased level, and/or inhibitingthe activity of a CLL marker polypeptide) according to the invention.

Whenever possible, the antibodies of the invention may be purchased fromcommercial sources. The antibodies of the invention may also begenerated using well-known methods. The skilled artisan will understandthat either full length CLL marker polypeptides or fragments thereof maybe used to generate the antibodies of the invention. A polypeptide to beused for generating an antibody of the invention may be partially orfully purified from a natural source, or may be produced usingrecombinant DNA techniques.

For example, a cDNA encoding a peptide according to the presentinvention, such as a peptide according to SEQ ID NO: 1 to SEQ ID NO:225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO:1016 polypeptide, or a variant or fragment thereof, can be expressed inprokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast,insect, or mammalian cells), after which the recombinant protein can bepurified and used to generate a monoclonal or polyclonal antibodypreparation that specifically bind the CLL marker polypeptide used togenerate the antibody according to the invention.

One of skill in the art will realize that the generation of two or moredifferent sets of monoclonal or polyclonal antibodies maximizes thelikelihood of obtaining an antibody with the specificity and affinityrequired for its intended use (e.g., ELISA, immunohistochemistry, invivo imaging, immunotoxin therapy). The antibodies are tested for theirdesired activity by known methods, in accordance with the purpose forwhich the antibodies are to be used (e.g., ELISA, immunohistochemistry,immunotherapy, etc.; for further guidance on the generation and testingof antibodies, see, e.g., Harlow and Lane, Antibodies: A LaboratoryManual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1988, new 2^(nd) edition 2013). For example, the antibodies may betested in ELISA assays or Western blots. After their initial in vitrocharacterization, antibodies intended for therapeutic or in vivodiagnostic use are tested according to known clinical testing methods.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a substantially homogeneous population of antibodies,i.e.; the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. The monoclonal antibodies herein specifically include“chimeric” antibodies in which a portion of the heavy and/or light chainis identical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is identical withor homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired antagonistic activity (U.S. Pat. No. 4,816,567, which is herebyincorporated in its entirety).

Monoclonal antibodies of the invention may be prepared using hybridomamethods. In a hybridoma method, a mouse or other appropriate host animalis typically immunized with an immunizing agent to elicit lymphocytesthat produce or are capable of producing antibodies that willspecifically bind to the immunizing agent. Alternatively, thelymphocytes may be immunized in vitro.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies).

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly, Fabfragments, can be accomplished using routine techniques known in theart. For instance, digestion can be performed using papain. Examples ofpapain digestion are described in WO 94/29348 and U.S. Pat. No.4,342,566. Papain digestion of antibodies typically produces twoidentical antigen binding fragments, called Fab fragments, each with asingle antigen binding site, and a residual Fc fragment. Pepsintreatment yields a F(ab′)₂ fragment and a pFc′ fragment.

The antibody fragments, whether attached to other sequences or not, canalso include insertions, deletions, substitutions, or other selectedmodifications of particular regions or specific amino acids residues,provided the activity of the fragment is not significantly altered orimpaired compared to the non-modified antibody or antibody fragment.These modifications can provide for some additional property, such as toremove/add amino acids capable of disulfide bonding, to increase itsbio-longevity, to alter its secretory characteristics, etc. In any case,the antibody fragment must possess a bioactive property, such as bindingactivity, regulation of binding at the binding domain, etc. Functionalor active regions of the antibody may be identified by mutagenesis of aspecific region of the protein, followed by expression and testing ofthe expressed polypeptide. Such methods are readily apparent to askilled practitioner in the art and can include site-specificmutagenesis of the nucleic acid encoding the antibody fragment.

The antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′ or other antigen-bindingsubsequences of antibodies) which contain minimal sequence derived fromnon-human immunoglobulin. Humanized antibodies include humanimmunoglobulins (recipient antibody) in which residues from acomplementary determining region (CDR) of the recipient are replaced byresidues from a CDR of a non-human species (donor antibody) such asmouse, rat or rabbit having the desired specificity, affinity andcapacity. In some instances, Fv framework (FR) residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin.

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed by substituting rodent CDRs or CDR sequencesfor the corresponding sequences of a human antibody. Accordingly, such“humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variabledomain has been substituted by the corresponding sequence from anon-human species. In practice, humanized antibodies are typically humanantibodies in which some CDR residues and possibly some FR residues aresubstituted by residues from analogous sites in rodent antibodies.

Transgenic animals (e.g., mice) that are capable, upon immunization, ofproducing a full repertoire of human antibodies in the absence ofendogenous immunoglobulin production can be employed. For example, ithas been described that the homozygous deletion of the antibody heavychain joining region gene in chimeric and germ-line mutant mice resultsin complete inhibition of endogenous antibody production. Transfer ofthe human germ-line immunoglobulin gene array in such germ-line mutantmice will result in the production of human antibodies upon antigenchallenge. Human antibodies can also be produced in phage displaylibraries.

Antibodies of the invention are preferably administered to a subject ina pharmaceutically acceptable carrier. Typically, an appropriate amountof a pharmaceutically-acceptable salt is used in the formulation torender the formulation isotonic. Examples of thepharmaceutically-acceptable carrier include saline, Ringer's solutionand dextrose solution. The pH of the solution is preferably from about 5to about 8, and more preferably from about 7 to about 7.5. Furthercarriers include sustained release preparations such as semipermeablematrices of solid hydrophobic polymers containing the antibody, whichmatrices are in the form of shaped articles, e.g., films, liposomes ormicroparticles. It will be apparent to those persons skilled in the artthat certain carriers may be more preferable depending upon, forinstance, the route of administration and concentration of antibodybeing administered.

The antibodies can be administered to the subject, patient, or cell byinjection (e.g., intravenous, intraperitoneal, subcutaneous,intramuscular), or by other methods such as infusion that ensure itsdelivery to the bloodstream in an effective form. The antibodies mayalso be administered by intratumoral or peritumoral routes, to exertlocal as well as systemic therapeutic effects. Local or intravenousinjection is preferred.

Effective dosages and schedules for administering the antibodies may bedetermined empirically, and making such determinations is within theskill in the art. Those skilled in the art will understand that thedosage of antibodies that must be administered will vary depending on,for example, the subject that will receive the antibody, the route ofadministration, the particular type of antibody used and other drugsbeing administered. A typical daily dosage of the antibody used alonemight range from about 1 (μg/kg to up to 100 mg/kg of body weight ormore per day, depending on the factors mentioned above. Followingadministration of an antibody for treating CLL, the efficacy of thetherapeutic antibody can be assessed in various ways well known to theskilled practitioner. s secondary to CLL

Because the peptides as mentioned in the Tables above (specifically theones associated with CLL) of the invention and thus their underlyingpolypeptides are highly expressed in CLL, and are expressed at rather toextremely low levels in normal cells, the inhibition of a proteinselected from the group consisting of APOBEC3D, CDK14, RASGRF1, CDCA7L,CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1, PARP3, TP53I11,B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5, ATP5G1,DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A, ELP3,NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4, COBLL1,TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3 expressionor of the activity thereof may be preferably integrated into atherapeutic strategy for treating or preventing CLL.

The principle of antisense therapy is based on the hypothesis thatsequence-specific suppression of gene expression (via transcription ortranslation) may be achieved by intra-cellular hybridization betweengenomic DNA or mRNA and a complementary antisense species. The formationof such a hybrid nucleic acid duplex interferes with transcription ofthe target tumor antigen-encoding genomic DNA, orprocessing/transport/translation and/or stability of the target tumorantigen mRNA.

Antisense nucleic acids can be delivered by a variety of approaches. Forexample, antisense oligonucleotides or anti-sense RNA can be directlyadministered (e.g., by intravenous injection) to a subject in a formthat allows uptake into tumor cells. Alternatively, viral or plasmidvectors that encode antisense RNA (or RNA fragments) can be introducedinto cells in vivo. Antisense effects can also be induced by sensesequences; however, the extent of phenotypic changes is highly variable.Phenotypic changes induced by effective antisense therapy are assessedaccording to changes in, e.g., target mRNA levels, target proteinlevels, and/or target protein activity levels.

In a specific example, inhibition of CLL marker function by antisensegene therapy may be accomplished by direct administration of antisenselung tumor marker RNA to a subject. The antisense tumor marker RNA maybe produced and isolated by any standard technique, but is most readilyproduced by in vitro transcription using an antisense tumor marker cDNAunder the control of a high efficiency promoter (e.g., the T7 promoter).Administration of anti-sense tumor marker RNA to cells can be carriedout by any of the methods for direct nucleic acid administrationdescribed below.

An alternative strategy for inhibiting the function of a proteinselected from the group consisting of APOBEC3D, CDK14, RASGRF1, CDCA7L,CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1, PARP3, TP53I11,B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5, ATP5G1,DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A, ELP3,NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4, COBLL1,TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3 using genetherapy involves intracellular expression of an anti-protein antibody ora portion of an anti-protein antibody. For example, the gene (or genefragment) encoding a monoclonal antibody that specifically binds to aprotein selected from the group consisting of APOBEC3D, CDK14, RASGRF1,CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1, PARP3,TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5,ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A,ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4,COBLL1, TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3 andinhibits its biological activity is placed under the transcriptionalcontrol of a specific (e.g., tissue- or tumor-specific) gene regulatorysequence, within a nucleic acid expression vector. The vector is thenadministered to the subject such that it is taken up by CLL cells orother cells, which then secrete the anti-protein antibody, and therebyblock biological activity of the respective polypeptide. Preferably,proteins are present on the cellular surface of CLL cancer cells.

In the methods described above, which include the administration anduptake of exogenous DNA into the cells of a subject (i.e., genetransduction or transfection), the nucleic acids of the presentinvention can be in the form of naked DNA or the nucleic acids can be ina vector for delivering the nucleic acids to the cells for inhibition ofCLL tumor marker protein expression. The vector can be a commerciallyavailable preparation, such as an adenovirus vector (QuantumBiotechnologies, Inc. (Laval, Quebec, Canada). Delivery of the nucleicacid or vector to cells can be via a variety of mechanisms. As oneexample, delivery can be via a liposome, using commercially availableliposome preparations such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-25 BRL,Inc., Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Germany) andTRANSFECTAM (Promega Biotec, Inc., Madison, Wis., US), as well as otherliposomes developed according to procedures standard in the art. Inaddition, the nucleic acid or vector of this invention can be deliveredin vivo by electroporation, the technology for which is available fromGenetronics, Inc. (San Diego, US) as well as by means of a SONOPORATIONmachine (ImaRx Pharmaceutical Corp., Tucson, Ariz., US).

As one example, vector delivery can be via a viral system, such as aretroviral vector system that can package a recombinant retroviralgenome. The recombinant retrovirus can then be used to infect andthereby deliver to the infected cells antisense nucleic acid thatinhibits expression of a protein selected from the group consisting ofAPOBEC3D, CDK14, RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP,ABCA6, DMXL1, PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296,BACH2, PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK,HSH2D, ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA,TUFM, EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7, CXorf21, ASUN,SL24D1, and TRAF3IP3. The exact method of introducing the alterednucleic acid into mammalian cells is, of course, not limited to the useof retroviral vectors. Other techniques are widely available for thisprocedure including the use of adenoviral vectors, adeno-associatedviral (AAV) vectors, lentiviral vectors, pseudotyped retroviral vectors.Physical transduction techniques can also be used, such as liposomedelivery and receptor-mediated and other endocytosis mechanisms. Thisinvention can be used in conjunction with any of these or other commonlyused gene transfer methods.

The antibodies may also be used for in vivo diagnostic assays.Generally, the antibody is labeled with a radionucleotide (such as¹¹¹In, ⁹⁹Tc, ¹⁴C, ¹³¹I, ³H, ³²P or ³⁵S) so that the tumor can belocalized using immunoscintiography. In one embodiment, antibodies orfragments thereof bind to the extracellular domains of two or moretargets of a protein selected from the group consisting of APOBEC3D,CDK14, RASGRF1, CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6,DMXL1, PARP3, TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2,PRR12, ZFAND5, ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK, HSH2D,ERP44, METTL7A, ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM,EIF6, CKAP4, COBLL1, TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, andTRAF3IP3, and the affinity value (Kd) is less than 1×100.

Antibodies for diagnostic use may be labeled with probes suitable fordetection by various imaging methods. Methods for detection of probesinclude, but are not limited to, fluorescence, light, confocal andelectron microscopy; magnetic resonance imaging and spectroscopy;fluoroscopy, computed tomography and positron emission tomography.Suitable probes include, but are not limited to, fluorescein, rhodamine,eosin and other fluorophores, radioisotopes, gold, gadolinium and otherlanthanides, paramagnetic iron, fluorine-18 and other positron-emittingradionuclides. Additionally, probes may be bi- or multi-functional andbe detectable by more than one of the methods listed. These antibodiesmay be directly or indirectly labeled with said probes. Attachment ofprobes to the antibodies includes covalent attachment of the probe,incorporation of the probe into the antibody, and the covalentattachment of a chelating compound for binding of probe, amongst otherswell recognized in the art. For immunohistochemistry, the disease tissuesample may be fresh or frozen or may be embedded in paraffin and fixedwith a preservative such as formalin. The fixed or embedded sectioncontains the sample are contacted with a labeled primary antibody andsecondary antibody, wherein the antibody is used to detect theexpression of the proteins in situ.

The present invention thus provides a peptide comprising a sequence thatis selected from the group of consisting of SEQ ID NO: 1 to SEQ ID NO:225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO:1016 or a variant thereof which is 90% homologous to SEQ ID NO: 1 to SEQID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ IDNO: 1016, or a variant thereof that will induce T cells cross-reactingwith said peptide.

The peptides of the invention have the ability to bind to a molecule ofthe human major histocompatibility complex (MHC) class-I and/or classII.

In the present invention, the term “homologous” refers to the degree ofidentity (see Percent Identity above) between sequences of two aminoacid sequences, i.e. peptide or polypeptide sequences. Theaforementioned “homology” is determined by comparing two sequencesaligned under optimal conditions over the sequences to be compared. Sucha sequence homology can be calculated by creating an alignment using,for example, the ClustalW algorithm. Commonly available sequenceanalysis software, more specifically, Vector NTI, GENETYX or otheranalysis tools are provided by public databases.

A person skilled in the art will be able to assess, whether T cellsinduced by a variant of a specific peptide will be able to cross-reactwith the peptide itself (Fong L, et al. Altered peptide ligandvaccination with Flt3 ligand expanded dendritic cells for tumorimmunotherapy. Proc Natl Acad Sci USA. 2001 Jul. 17; 98(15):8809-14;Zaremba S, et al. Identification of an enhancer agonist cytotoxic Tlymphocyte peptide from human carcinoembryonic antigen. Cancer Res. 1997Oct. 15; 57(20):4570-7; Colombetti S, et al. Impact of orthologousmelan-A peptide immunizations on the anti-self melan-A/HLA-A2 T cellcross-reactivity. J Immunol. 2006 Jun. 1; 176(11):6560-7; Appay V, etal. Decreased specific CD8+ T cell cross-reactivity of antigenrecognition following vaccination with Melan-A peptide. Eur J Immunol.2006 July; 36(7):1805-14).

By a “variant” of the given amino acid sequence the inventors mean thatthe side chains of, for example, one or two of the amino acid residuesare altered (for example by replacing them with the side chain ofanother naturally occurring amino acid residue or some other side chain)such that the peptide is still able to bind to an HLA molecule insubstantially the same way as a peptide consisting of the given aminoacid sequence in consisting of SEQ ID NO: 1 to SEQ ID NO: 225, SEQ IDNO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016. Forexample, a peptide may be modified so that it at least maintains, if notimproves, the ability to interact with and bind to the binding groove ofa suitable MHC molecule, such as HLA-A*02 or -DR, and in that way it atleast maintains, if not improves, the ability to bind to the TCR ofactivated CTL.

These CTL can subsequently cross-react with cells and kill cells thatexpress a polypeptide that contains the natural amino acid sequence ofthe cognate peptide as defined in the aspects of the invention. As canbe derived from the scientific literature (Godkin A, et al. Use ofeluted peptide sequence data to identify the binding characteristics ofpeptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8(DQ 3.2). Int Immunol. 1997 June; 9(6):905-11) and databases (RammenseeH. et al. SYFPEITHI: database for MHC ligands and peptide motifs.Immunogenetics. 1999 November; 50(3-4):213-9), certain positions of HLAbinding peptides are typically anchor residues forming a core sequencefitting to the binding motif of the HLA receptor, which is defined bypolar, electrophysical, hydrophobic and spatial properties of thepolypeptide chains constituting the binding groove. Thus, one skilled inthe art would be able to modify the amino acid sequences set forth inSEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQID NO: 543 to SEQ ID NO: 1016, by maintaining the known anchor residues,and would be able to determine whether such variants maintain theability to bind MHC class I or II molecules. The variants of the presentinvention retain the ability to bind to the TCR of activated CTL, whichcan subsequently cross-react with—and kill cells that express apolypeptide containing the natural amino acid sequence of the cognatepeptide as defined in the aspects of the invention.

The amino acid residues that do not substantially contribute tointeractions with the T-cell receptor can be modified by replacementwith another amino acid whose incorporation does not substantiallyaffect T-cell reactivity and does not eliminate binding to the relevantMHC. Thus, apart from the proviso given, the peptide of the inventionmay be any peptide (by which term the inventors include oligopeptide orpolypeptide), which includes the amino acid sequences or a portion orvariant thereof as given.

Longer peptides may also be suitable. It is also possible, that MHCclass I epitopes, although usually between 8 and 11 amino acids long,are generated by peptide processing from longer peptides or proteinsthat include the actual epitope. It is preferred that the residues thatflank the actual epitope are residues that do not substantially affectproteolytic cleavage necessary to expose the actual epitope duringprocessing.

Accordingly, the present invention also provides peptides and variantsof MHC class I epitopes wherein the peptide or variant has an overalllength of between 8 and 100, preferably between 8 and 30, and mostpreferred between 8 and 14, namely 8, 9, 10, 11, 12, 13, 14 amino acids,in case of the class II binding peptides the length can also be 15, 16,17, 18, 19, 20, 21 or 22 amino acids.

Of course, the peptide or variant according to the present inventionwill have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class I. Binding of a peptide or avariant to a MHC complex may be tested by methods known in the art.

In a particularly preferred embodiment of the invention the peptideconsists or consists essentially of an amino acid sequence according toSEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 to SEQ ID NO: 542 or SEQID NO: 543 to SEQ ID NO: 1016.

“Consisting essentially of” shall mean that a peptide according to thepresent invention, in addition to the sequence according to any of SEQID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226: to SEQ ID NO: 542 or SEQ IDNO: 543 to SEQ ID NO: 1016 or a variant thereof contains additional N-and/or C-terminally located stretches of amino acids that are notnecessarily forming part of the peptide that functions as an epitope forMHC molecules epitope.

Nevertheless, these stretches can be important to provide an efficientintroduction of the peptide according to the present invention into thecells. In one embodiment of the present invention, the peptide is afusion protein which comprises, for example, the 80 N-terminal aminoacids of the HLA-DR antigen-associated invariant chain (p33, in thefollowing “Ii”) as derived from the NCBI, GenBank Accession numberX00497. In other fusions, the peptides of the present invention can befused to an antibody as described herein, or a functional part thereof,in particular into a sequence of an antibody, so as to be specificallytargeted by said antibody, or, for example, to or into an antibody thatis specific for dendritic cells.

In addition, the peptide or variant may be modified further to improvestability and/or binding to MHC molecules in order to elicit a strongerimmune response. Methods for such an optimization of a peptide sequenceare well known in the art and include, for example, the introduction ofreverse peptide bonds or non-peptide bonds.

In a reverse peptide bond amino acid residues are not joined by peptide(—CO—NH—) linkages but the peptide bond is reversed. Such retro-inversopeptidomimetics may be made using methods known in the art, for examplesuch as those described in Meziere et al (1997) J. Immunol. 159,3230-3237, incorporated herein by reference. This approach involvesmaking pseudopeptides containing changes involving the backbone, and notthe orientation of side chains. Meziere et al (1997) show that for MHCbinding and T helper cell responses, these pseudopeptides are useful.Retro-inverse peptides, which contain NH—CO bonds instead of CO—NHpeptide bonds, are much more resistant to proteolysis.

A non-peptide bond is, for example, —CH₂—NH, —CH₂S—, —CH₂CH₂—, —CH═CH—,—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—. U.S. Pat. No. 4,897,445 provides amethod for the solid phase synthesis of non-peptide bonds (—CH₂—NH) inpolypeptide chains which involves polypeptides synthesized by standardprocedures and the non-peptide bond synthesized by reacting an aminoaldehyde and an amino acid in the presence of NaCNBH₃.

Peptides comprising the sequences described above may be synthesizedwith additional chemical groups present at their amino and/or carboxytermini, to enhance the stability, bioavailability, and/or affinity ofthe peptides. For example, hydrophobic groups such as carbobenzoxyl,dansyl, or t-butyloxycarbonyl groups may be added to the peptides' aminotermini. Likewise, an acetyl group or a 9-fluorenylmethoxy-carbonylgroup may be placed at the peptides' amino termini. Additionally, thehydrophobic group, t-butyloxycarbonyl, or an amido group may be added tothe peptides' carboxy termini.

Further, the peptides of the invention may be synthesized to alter theirsteric configuration. For example, the D-isomer of one or more of theamino acid residues of the peptide may be used, rather than the usualL-isomer. Still further, at least one of the amino acid residues of thepeptides of the invention may be substituted by one of the well-knownnon-naturally occurring amino acid residues. Alterations such as thesemay serve to increase the stability, bioavailability and/or bindingaction of the peptides of the invention.

Similarly, a peptide or variant of the invention may be modifiedchemically by reacting specific amino acids either before or aftersynthesis of the peptide. Examples for such modifications are well knownin the art and are summarized e.g. in R. Lundblad, Chemical Reagents forProtein Modification, 3rd ed. CRC Press, 2005, which is incorporatedherein by reference. Chemical modification of amino acids includes butis not limited to, modification by acylation, amidination,pyridoxylation of lysine, reductive alkylation, trinitrobenzylation ofamino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS), amidemodification of carboxyl groups and sulphydryl modification by performicacid oxidation of cysteine to cysteic acid, formation of mercurialderivatives, formation of mixed disulphides with other thiol compounds,reaction with maleimide, carboxymethylation with iodoacetic acid oriodoacetamide and carbamoylation with cyanate at alkaline pH, althoughwithout limitation thereto. In this regard, the skilled person isreferred to Chapter 15 of Current Protocols In Protein Science, Eds.Coligan et al. (John Wiley and Sons NY 1995-2000) for more extensivemethodology relating to chemical modification of proteins.

Briefly, modification of e.g. arginyl residues in proteins is oftenbased on the reaction of vicinal dicarbonyl compounds such asphenylglyoxal, 2,3-butanedione, and 1,2-cyclohexanedione to form anadduct. Another example is the reaction of methylglyoxal with arginineresidues. Cysteine can be modified without concomitant modification ofother nucleophilic sites such as lysine and histidine. As a result, alarge number of reagents are available for the modification of cysteine.The websites of companies such as Sigma-Aldrich provide information onspecific reagents.

Selective reduction of disulfide bonds in proteins is also common.Disulfide bonds can be formed and oxidized during the heat treatment ofbiopharmaceuticals.

Woodward's Reagent K may be used to modify specific glutamic acidresidues. N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide can be usedto form intra-molecular crosslinks between a lysine residue and aglutamic acid residue.

For example, diethylpyrocarbonate is a reagent for the modification ofhistidyl residues in proteins. Histidine can also be modified using4-hydroxy-2-nonenal.

The reaction of lysine residues and other a-amino groups is, forexample, useful in binding of peptides to surfaces or the cross-linkingof proteins/peptides. Lysine is the site of attachment ofpoly(ethylene)glycol and the major site of modification in theglycosylation of proteins.

Methionine residues in proteins can be modified with e.g. iodoacetamide,bromoethylamine, and chloramine T.

Tetranitromethane and N-acetylimidazole can be used for the modificationof tyrosyl residues. Cross-linking via the formation of dityrosine canbe accomplished with hydrogen peroxide/copper ions.

Recent studies on the modification of tryptophan have usedN-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole (BPNS-skatole).

Successful modification of therapeutic proteins and peptides with PEG isoften associated with an extension of circulatory half-life whilecross-linking of proteins with glutaraldehyde, polyethyleneglycoldiacrylate and formaldehyde is used for the preparation of hydrogels.Chemical modification of allergens for immunotherapy is often achievedby carbamylation with potassium cyanate.

A peptide or variant, wherein the peptide is modified or includesnon-peptide bonds is a preferred embodiment of the invention. Generally,peptides and variants (at least those containing peptide linkagesbetween amino acid residues) may be synthesized by the Fmoc-polyamidemode of solid-phase peptide synthesis as disclosed by Lukas et al.(Solid-phase peptide synthesis under continuous-flow conditions. ProcNatl Acad Sci USA. May 1981; 78(5): 2791-2795) and references therein.Temporary N-amino group protection is afforded by the9-fluorenylmethyloxycarbonyl (Fmoc) group. Repetitive cleavage of thishighly base-labile protecting group is done using 20% piperidine in N,N-dimethylformamide. Side-chain functionalities may be protected astheir butyl ethers (in the case of serine threonine and tyrosine), butylesters (in the case of glutamic acid and aspartic acid),butyloxycarbonyl derivative (in the case of lysine and histidine),trityl derivative (in the case of cysteine) and4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case ofarginine). Where glutamine or asparagine are C-terminal residues, use ismade of the 4,4′-dimethoxybenzhydryl group for protection of the sidechain amido functionalities. The solid-phase support is based on apolydimethyl-acrylamide polymer constituted from the three monomersdimethylacrylamide (backbone-monomer), bisacryloylethylene diamine(cross linker) and acryloylsarcosine methyl ester (functionalizingagent). The peptide-to-resin cleavable linked agent used is theacid-labile 4-hydroxymethyl-phenoxyacetic acid derivative. All aminoacid derivatives are added as their preformed symmetrical anhydridederivatives with the exception of asparagine and glutamine, which areadded using a reversed N, N-dicyclohexyl-carbodiimide/1hydroxybenzotriazole mediated coupling procedure. All coupling anddeprotection reactions are monitored using ninhydrin, trinitrobenzenesulphonic acid or isotin test procedures. Upon completion of synthesis,peptides are cleaved from the resin support with concomitant removal ofside-chain protecting groups by treatment with 95% trifluoroacetic acidcontaining a 50% scavenger mix. Scavengers commonly used includeethandithiol, phenol, anisole and water, the exact choice depending onthe constituent amino acids of the peptide being synthesized. Also acombination of solid phase and solution phase methodologies for thesynthesis of peptides is possible (see, for example, Bruckdorfer et al.,2004, and the references as cited therein).

Trifluoroacetic acid is removed by evaporation in vacuo, with subsequenttrituration with diethyl ether affording the crude peptide. Anyscavengers present are removed by a simple extraction procedure which onlyophilisation of the aqueous phase affords the crude peptide free ofscavengers. Reagents for peptide synthesis are generally available frome.g. Calbiochem-Novabiochem (UK) Ltd, Nottingham NG7 2QJ, UK.

Purification may be performed by any one, or a combination of,techniques such as re-crystallization, size exclusion chromatography,ion-exchange chromatography, hydrophobic interaction chromatography and(usually) reverse-phase high performance liquid chromatography usinge.g. acetonitril/water gradient separation.

Analysis of peptides may be carried out using thin layer chromatography,electrophoresis, in particular capillary electrophoresis, solid phaseextraction (CSPE), reverse-phase high performance liquid chromatography,amino-acid analysis after acid hydrolysis and by fast atom bombardment(FAB) mass spectrometric analysis, as well as MALDI and ESI-Q-TOF massspectrometric analysis.

A further aspect of the invention provides a nucleic acid (for example apolynucleotide) encoding a peptide or peptide variant of the invention.The polynucleotide may be, for example, DNA, cDNA, PNA, RNA orcombinations thereof, either single- and/or double-stranded, or nativeor stabilized forms of polynucleotides, such as, for example,polynucleotides with a phosphorothioate backbone and it may or may notcontain introns so long as it codes for the peptide. Of course, onlypeptides that contain naturally occurring amino acid residues joined bynaturally occurring peptide bonds are encodable by a polynucleotide. Astill further aspect of the invention provides an expression vectorcapable of expressing a polypeptide according to the invention.

A variety of methods have been developed to link polynucleotides,especially DNA, to vectors for example via complementary cohesivetermini. For instance, complementary homopolymer tracts can be added tothe DNA segment to be inserted to the vector DNA. The vector and DNAsegment are then joined by hydrogen bonding between the complementaryhomopolymeric tails to form recombinant DNA molecules.

Synthetic linkers containing one or more restriction sites provide analternative method of joining the DNA segment to vectors. Syntheticlinkers containing a variety of restriction endonuclease sites arecommercially available from a number of sources including InternationalBiotechnologies Inc. New Haven, Conn., USA.

A desirable method of modifying the DNA encoding the polypeptide of theinvention employs the polymerase chain reaction as disclosed by Saiki RK, et al. (Diagnosis of sickle cell anemia and beta-thalassemia withenzymatically amplified DNA and nonradioactive allele-specificoligonucleotide probes. N Engl J Med. 1988 Sep. 1; 319(9):537-41). Thismethod may be used for introducing the DNA into a suitable vector, forexample by engineering in suitable restriction sites, or it may be usedto modify the DNA in other useful ways as is known in the art. If viralvectors are used, pox- or adenovirus vectors are preferred.

The DNA (or in the case of retroviral vectors, RNA) may then beexpressed in a suitable host to produce a polypeptide comprising thepeptide or variant of the invention. Thus, the DNA encoding the peptideor variant of the invention may be used in accordance with knowntechniques, appropriately modified in view of the teachings containedherein, to construct an expression vector, which is then used totransform an appropriate host cell for the expression and production ofthe polypeptide of the invention. Such techniques include thosedisclosed in U.S. Pat. Nos. 4,440,859, 4,530,901, 4,582,800, 4,677,063,4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075, and 4,810,648.

The DNA (or in the case of retroviral vectors, RNA) encoding thepolypeptide constituting the compound of the invention may be joined toa wide variety of other DNA sequences for introduction into anappropriate host. The companion DNA will depend upon the nature of thehost, the manner of the introduction of the DNA into the host, andwhether episomal maintenance or integration is desired.

Generally, the DNA is inserted into an expression vector, such as aplasmid, in proper orientation and correct reading frame for expression.If necessary, the DNA may be linked to the appropriate transcriptionaland translational regulatory control nucleotide sequences recognized bythe desired host, although such controls are generally available in theexpression vector. The vector is then introduced into the host throughstandard techniques. Generally, not all of the hosts will be transformedby the vector. Therefore, it will be necessary to select for transformedhost cells. One selection technique involves incorporating into theexpression vector a DNA sequence, with any necessary control elements,that codes for a selectable trait in the transformed cell, such asantibiotic resistance.

Alternatively, the gene for such selectable trait can be on anothervector, which is used to co-transform the desired host cell.

Host cells that have been transformed by the recombinant DNA of theinvention are then cultured for a sufficient time and under appropriateconditions known to those skilled in the art in view of the teachingsdisclosed herein to permit the expression of the polypeptide, which canthen be recovered.

Many expression systems are known, including bacteria (for example E.coli and Bacillus subtilis), yeasts (for example Saccharomycescerevisiae), filamentous fungi (for example Aspergillus spec.), plantcells, animal cells and insect cells. Preferably, the system can bemammalian cells such as CHO cells available from the ATCC Cell BiologyCollection.

A typical mammalian cell vector plasmid for constitutive expressioncomprises the CMV or SV40 promoter with a suitable poly A tail and aresistance marker, such as neomycin. One example is pSVL available fromPharmacia, Piscataway, N.J., USA. An example of an inducible mammalianexpression vector is pMSG, also available from Pharmacia. Useful yeastplasmid vectors are pRS403-406 and pRS413-416 and are generallyavailable from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA.Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integratingplasmids (YIps) and incorporate the yeast selectable markers HIS3, TRP1,LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps).CMV promoter-based vectors (for example from Sigma-Aldrich) providetransient or stable expression, cytoplasmic expression or secretion, andN-terminal or C-terminal tagging in various combinations of FLAG,3×FLAG, c-myc or MAT. These fusion proteins allow for detection,purification and analysis of recombinant protein. Dual-tagged fusionsprovide flexibility in detection.

The strong human cytomegalovirus (CMV) promoter regulatory region drivesconstitutive protein expression levels as high as 1 mg/L in COS cells.For less potent cell lines, protein levels are typically ˜0.1 mg/L. Thepresence of the SV40 replication origin will result in high levels ofDNA replication in SV40 replication permissive COS cells. CMV vectors,for example, can contain the pMB1 (derivative of pBR322) origin forreplication in bacterial cells, the b-lactamase gene for ampicillinresistance selection in bacteria, hGH polyA, and the f1 origin. Vectorscontaining the preprotrypsin leader (PPT) sequence can direct thesecretion of FLAG fusion proteins into the culture medium forpurification using ANTI-FLAG antibodies, resins, and plates. Othervectors and expression systems are well known in the art for use with avariety of host cells.

In another embodiment two or more peptides or peptide variants of theinvention are encoded and thus expressed in a successive order (similarto “beads on a string” constructs). In doing so, the peptides or peptidevariants may be linked or fused together by stretches of linker aminoacids, such as for example LLLLLL, or may be linked without anyadditional peptide(s) between them.

The present invention also relates to a host cell transformed with apolynucleotide vector construct of the present invention. The host cellcan be either prokaryotic or eukaryotic. Bacterial cells may bepreferred prokaryotic host cells in some circumstances and typically area strain of E. coli such as, for example, the E. coli strains DH5available from Bethesda Research Laboratories Inc., Bethesda, Md., USA,and RR1 available from the American Type Culture Collection (ATCC) ofRockville, Md., USA (No ATCC 31343). Preferred eukaryotic host cellsinclude yeast, insect and mammalian cells, preferably vertebrate cellssuch as those from a mouse, rat, monkey or human fibroblastic and coloncell lines. Yeast host cells include YPH499, YPH500 and YPH501, whichare generally available from Stratagene Cloning Systems, La Jolla,Calif. 92037, USA. Preferred mammalian host cells include Chinesehamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swissmouse embryo cells NIH/3T3 available from the ATCC as CRL 1658, monkeykidney-derived COS-1 cells available from the ATCC as CRL 1650 and 293cells which are human embryonic kidney cells. Preferred insect cells areSf9 cells which can be transfected with baculovirus expression vectors.An overview regarding the choice of suitable host cells for expressioncan be found in, for example, the textbook of Paulina Balbás and ArgeliaLorence “Methods in Molecular Biology Recombinant Gene Expression,Reviews and Protocols,” Part One, Second Edition, ISBN978-1-58829-262-9, and other literature known to the person of skill.

Transformation of appropriate cell hosts with a DNA construct of thepresent invention is accomplished by well-known methods that typicallydepend on the type of vector used. With regard to transformation ofprokaryotic host cells, see, for example, Cohen et al (1972) Proc. Natl.Acad. Sci. USA 69, 2110, and Sambrook et al (1989) Molecular Cloning, ALaboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor,N.Y. Transformation of yeast cells is described in Sherman et al (1986)Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor, N.Y.The method of Beggs (1978) Nature 275, 104-109 is also useful. Withregard to vertebrate cells, reagents useful in transfecting such cells,for example calcium phosphate and DEAE-dextran or liposome formulations,are available from Stratagene Cloning Systems, or Life TechnologiesInc., Gaithersburg, Md. 20877, USA. Electroporation is also useful fortransforming and/or transfecting cells and is well known in the art fortransforming yeast cell, bacterial cells, insect cells and vertebratecells.

Successfully transformed cells, i.e. cells that contain a DNA constructof the present invention, can be identified by well-known techniquessuch as PCR. Alternatively, the presence of the protein in thesupernatant can be detected using antibodies.

It will be appreciated that certain host cells of the invention areuseful in the preparation of the peptides of the invention, for examplebacterial, yeast and insect cells. However, other host cells may beuseful in certain therapeutic methods. For example, antigen-presentingcells, such as dendritic cells, may usefully be used to express thepeptides of the invention such that they may be loaded into appropriateMHC molecules. Thus, the current invention provides a host cellcomprising a nucleic acid or an expression vector according to theinvention.

In a preferred embodiment the host cell is an antigen presenting cell,in particular a dendritic cell or antigen presenting cell. APCs loadedwith a recombinant fusion protein containing prostatic acid phosphatase(PAP) were approved by the U.S. Food and Drug Administration (FDA) onApr. 29, 2010, to treat asymptomatic or minimally symptomatic metastaticHRPC (Sipuleucel-T) (Small E J, et al. Placebo-controlled phase IIItrial of immunologic therapy with sipuleucel-T (APC8015) in patientswith metastatic, asymptomatic hormone refractory prostate cancer. J ClinOncol. 2006 Jul. 1; 24(19):3089-94. Rini et al. Combinationimmunotherapy with prostatic acid phosphatase pulsed antigen-presentingcells (provenge) plus bevacizumab in patients with serologic progressionof prostate cancer after definitive local therapy. Cancer. 2006 Jul. 1;107(1):67-74).

A further aspect of the invention provides a method of producing apeptide or its variant, the method comprising culturing a host cell andisolating the peptide from the host cell or its culture medium.

In another embodiment the peptide, the nucleic acid or the expressionvector of the invention are used in medicine. For example, the peptideor its variant may be prepared for intravenous (i.v.) injection,sub-cutaneous (s.c.) injection, intradermal (i.d.) injection,intraperitoneal (i.p.) injection, intramuscular (i.m.) injection.Preferred methods of peptide injection include s.c., i.d., i.p., i.m.,and i.v. Preferred methods of DNA injection include i.d., i.m., s.c.,i.p. and i.v. Doses of e.g. between 50 μg and 1.5 mg, preferably 125 μgto 500 μg, of peptide or DNA may be given and will depend on therespective peptide or DNA. Dosages of this range were successfully usedin previous trials (Walter et al Nature Medicine 18, 1254-1261 (2012)).

Another aspect of the present invention includes an in vitro method forproducing activated T cells, the method comprising contacting in vitro Tcells with antigen loaded human MHC molecules expressed on the surfaceof a suitable antigen-presenting cell for a period of time sufficient toactivate the T cell in an antigen specific manner, wherein the antigenis a peptide according to the invention. Preferably a sufficient amountof the antigen is used with an antigen-presenting cell.

Preferably the mammalian cell lacks or has a reduced level or functionof the TAP peptide transporter. Suitable cells that lack the TAP peptidetransporter include T2, RMA-S and Drosophila cells. TAP is thetransporter associated with antigen processing.

The human peptide loading deficient cell line T2 is available from theAmerican Type Culture Collection, 12301 Parklawn Drive, Rockville, Md.20852, USA under Catalogue No CRL 1992; the Drosophila cell lineSchneider line 2 is available from the ATCC under Catalogue No CRL19863; the mouse RMA-S cell line is described in Karre et al 1985(Ljunggren, H.-G., and K. Karre. 1985. J. Exp. Med. 162:1745).

Preferably, the host cell before transfection expresses substantially noMHC class I molecules. It is also preferred that the stimulator cellexpresses a molecule important for providing a co-stimulatory signal forT-cells such as any of B7.1, B7.2, ICAM-1 and LFA 3. The nucleic acidsequences of numerous MHC class I molecules and of the co-stimulatormolecules are publicly available from the GenBank and EMBL databases.

In case of a MHC class I epitope being used as an antigen, the T cellsare CD8-positive CTLs.

If an antigen-presenting cell is transfected to express such an epitope,preferably the cell comprises an expression vector capable of expressinga peptide containing SEQ ID NO: 1 to SEQ ID NO: 225, SEQ ID NO: 226 toSEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, or a variant aminoacid sequence thereof.

A number of other methods may be used for generating CTL in vitro. Forexample, autologous tumor-infiltrating lymphocytes can be used in thegeneration of CTL. Plebanski et al (1995) (Induction of peptide-specificprimary cytotoxic T lymphocyte responses from human peripheral blood.Eur J Immunol. 1995 June; 25(6):1783-7) make use of autologousperipheral blood lymphocytes (PLBs) in the preparation of CTL.Furthermore, the production of autologous CTL by pulsing dendritic cellswith peptide or polypeptide, or via infection with recombinant virus ispossible. Also, B cells can be used in the production of autologous CTL.In addition, macrophages pulsed with peptide or polypeptide, or infectedwith recombinant virus, may be used in the preparation of autologousCTL. S. Walter et al. 2003 (Cutting edge: predetermined avidity of humanCD8 T cells expanded on calibrated MHC/anti-CD28-coated microspheres. JImmunol. 2003 Nov. 15; 171(10):4974-8) describe the in vitro priming ofT cells by using artificial antigen presenting cells (aAPCs), which isalso a suitable way for generating T cells against the peptide ofchoice. In the present invention, aAPCs were generated by the couplingof preformed MHC:peptide complexes to the surface of polystyreneparticles (microbeads) by biotin:streptavidin biochemistry. This systempermits the exact control of the MHC density on aAPCs, which allows toselectively elicit high- or low-avidity antigen-specific T cellresponses with high efficiency from blood samples. Apart fromMHC:peptide complexes, aAPCs should carry other proteins withco-stimulatory activity like anti-CD28 antibodies coupled to theirsurface. Furthermore such aAPC-based systems often require the additionof appropriate soluble factors, e. g. cytokines, like interleukin-12.

Allogeneic cells may also be used in the preparation of T cells and amethod is described in detail in WO 97/26328, incorporated herein byreference. For example, in addition to Drosophila cells and T2 cells,other cells may be used to present antigens such as CHO cells,baculovirus-infected insect cells, bacteria, yeast, vaccinia-infectedtarget cells. In addition plant viruses may be used (see, for example,Porta et al. (1994) Development of cowpea mosaic virus as ahigh-yielding system for the presentation of foreign peptides. Virology.1994 Aug. 1; 202(2):949-55) which describes the development of cowpeamosaic virus as a high-yielding system for the presentation of foreignpeptides.

The activated T cells that are directed against the peptides of theinvention are useful in therapy. Thus, a further aspect of the inventionprovides activated T cells obtainable by the foregoing methods of theinvention.

Activated T cells, which are produced by the above method, willselectively recognize a cell that aberrantly expresses a polypeptidethat comprises an amino acid sequence of SEQ ID NO: 1 to SEQ ID NO: 225,SEQ ID NO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016.

Preferably, the T cell recognizes the cell by interacting through itsTCR with the HLA/peptide-complex (for example, binding). The T cells areuseful in a method of killing target cells in a patient whose targetcells aberrantly express a polypeptide comprising an amino acid sequenceof the invention wherein the patient is administered an effective numberof the activated T cells. The T cells that are administered to thepatient may be derived from the patient and activated as described above(i.e. they are autologous T cells). Alternatively, the T cells are notfrom the patient but are from another individual. Of course, it ispreferred if the individual is a healthy individual. By “healthyindividual” the inventors mean that the individual is generally in goodhealth, preferably has a competent immune system and, more preferably,is not suffering from any disease that can be readily tested for, anddetected.

In vivo, the target cells for the CD8-positive T cells according to thepresent invention can be cells of the tumor (which sometimes express MHCclass II) and/or stromal cells surrounding the tumor (tumor cells)(which sometimes also express MHC class II; (Dengjel et al., 2006)).

The T cells of the present invention may be used as active ingredientsof a therapeutic composition. Thus, the invention also provides a methodof killing target cells in a patient whose target cells aberrantlyexpress a polypeptide comprising an amino acid sequence of theinvention, the method comprising administering to the patient aneffective number of T cells as defined above.

By “aberrantly expressed” the inventors also mean that the polypeptideis over-expressed compared to normal levels of expression or that thegene is silent in the tissue from which the tumor is derived but in thetumor it is expressed. By “over-expressed” the inventors mean that thepolypeptide is present at a level at least 1.2-fold of that present innormal tissue; preferably at least 2-fold, and more preferably at least5-fold or 10-fold the level present in normal tissue.

T cells may be obtained by methods known in the art, e.g. thosedescribed above.

Protocols for this so-called adoptive transfer of T cells are well knownin the art. Reviews can be found in: Gattinoni L, et al. Adoptiveimmunotherapy for cancer: building on success. Nat Rev Immunol. 2006May; 6(5):383-93. Review. and Morgan R A, et al. Cancer regression inpatients after transfer of genetically engineered lymphocytes. Science.2006 Oct. 6; 314(5796):126-9).

Any molecule of the invention, i.e. the peptide, nucleic acid, antibody,expression vector, cell, activated CTL, T-cell receptor or the nucleicacid encoding it is useful for the treatment of disorders, characterizedby cells escaping an immune response. Therefore any molecule of thepresent invention may be used as medicament or in the manufacture of amedicament. The molecule may be used by itself or combined with othermolecule(s) of the invention or (a) known molecule(s).

Preferably, the medicament of the present invention is a vaccine. It maybe administered directly into the patient, into the affected organ orsystemically i.d., i.m., s.c., i.p. and i.v., or applied ex vivo tocells derived from the patient or a human cell line which aresubsequently administered to the patient, or used in vitro to select asubpopulation of immune cells derived from the patient, which are thenre-administered to the patient. If the nucleic acid is administered tocells in vitro, it may be useful for the cells to be transfected so asto co-express immune-stimulating cytokines, such as interleukin-2. Thepeptide may be substantially pure, or combined with animmune-stimulating adjuvant (see below) or used in combination withimmune-stimulatory cytokines, or be administered with a suitabledelivery system, for example liposomes. The peptide may also beconjugated to a suitable carrier such as keyhole limpet haemocyanin(KLH) or mannan (see WO 95/18145 and Longenecker, 1993). The peptide mayalso be tagged, may be a fusion protein, or may be a hybrid molecule.The peptides whose sequence is given in the present invention areexpected to stimulate CD4 or CD8 T cells. However, stimulation of CD8CTLs is more efficient in the presence of help provided by CD4 T-helpercells. Thus, for MHC Class I epitopes that stimulate CD8 CTL the fusionpartner or sections of a hybrid molecule suitably provide epitopes whichstimulate CD4-positive T cells. CD4- and CD8-stimulating epitopes arewell known in the art and include those identified in the presentinvention.

In one aspect, the vaccine comprises at least one peptide having theamino acid sequence set forth SEQ ID No. 1 to SEQ ID No. 1016, and atleast one additional peptide, preferably two to 50, more preferably twoto 25, even more preferably two to 20 and most preferably two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen or eighteen peptides. Thepeptide(s) may be derived from one or more specific TAAs and may bind toMHC class I molecules.

In another aspect, the vaccine comprises at least one peptide having theamino acid sequence set forth in SEQ ID NO: 1 to SEQ ID NO: 225, SEQ IDNO: 226 to SEQ ID NO: 542 or SEQ ID NO: 543 to SEQ ID NO: 1016, and atleast one additional peptide, preferably two to 50, more preferably twoto 25, even more preferably two to 20 and most preferably two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen or eighteen peptides. Thepeptide(s) may be derived from one or more specific TAAs and may bind toMHC class I molecules.

The polynucleotide may be substantially pure, or contained in a suitablevector or delivery system. The nucleic acid may be DNA, cDNA, PNA, RNAor a combination thereof. Methods for designing and introducing such anucleic acid are well known in the art. An overview is provided by e.g.(Pascolo et al., Human peripheral blood mononuclear cells transfectedwith messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes invitro. Cell Mol Life Sci. 2005 August; 62(15):1755-62). Polynucleotidevaccines are easy to prepare, but the mode of action of these vectors ininducing an immune response is not fully understood. Suitable vectorsand delivery systems include viral DNA and/or RNA, such as systems basedon adenovirus, vaccinia virus, retroviruses, herpes virus,adeno-associated virus or hybrids containing elements of more than onevirus. Non-viral delivery systems include cationic lipids and cationicpolymers and are well known in the art of DNA delivery. Physicaldelivery, such as via a “gene-gun” may also be used. The peptide orpeptides encoded by the nucleic acid may be a fusion protein, forexample with an epitope that stimulates T cells for the respectiveopposite CDR as noted above.

The medicament of the invention may also include one or more adjuvants.Adjuvants are substances that non-specifically enhance or potentiate theimmune response (e.g., immune responses mediated by CTLs and helper-T(TH) cells to an antigen, and would thus be considered useful in themedicament of the present invention. Suitable adjuvants include, but arenot limited to, 1018 ISS, aluminium salts, AMPLIVAX®, AS15, BCG,CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLR5 ligands derived fromflagellin, FLT3 ligand, GM-CSF, IC30, IC31, Imiquimod (ALDARA®),resiquimod, ImuFact IMP321, Interleukins as IL-2, IL-13, IL-21,Interferon-alpha or -beta, or pegylated derivatives thereof, IS Patch,ISS, ISCOMATRIX, ISCOMs, JuvImmune®, LipoVac, MALP2, MF59,monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, MontanideISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions,OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vector system,poly(lactid co-glycolid) [PLG]-based and dextran microparticles,talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D,VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, which isderived from saponin, mycobacterial extracts and synthetic bacterialcell wall mimics, and other proprietary adjuvants such as Ribi's Detox,Quil, or Superfos. Adjuvants such as Freund's or GM-CSF are preferred.Several immunological adjuvants (e.g., MF59) specific for dendriticcells and their preparation have been described previously (Allison andKrummel, 1995 The Yin and Yang of T cell costimulation. Science. 1995Nov. 10; 270(5238):932-3. Review). Also cytokines may be used. Severalcytokines have been directly linked to influencing dendritic cellmigration to lymphoid tissues (e.g., TNF-), accelerating the maturationof dendritic cells into efficient antigen-presenting cells forT-lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Pat. No. 5,849,589,specifically incorporated herein by reference in its entirety) andacting as immunoadjuvants (e.g., IL-12, IL-15, IL-23, IL-7, IFN-alpha.IFN-beta) (Gabrilovich, 1996 Production of vascular endothelial growthfactor by human tumors inhibits the functional maturation of dendriticcells Nat Med. 1996 October; 2(10):1096-103).

CpG immunostimulatory oligonucleotides have also been reported toenhance the effects of adjuvants in a vaccine setting. Without beingbound by theory, CpG oligonucleotides act by activating the innate(non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9.CpG triggered TLR9 activation enhances antigen-specific humoral andcellular responses to a wide variety of antigens, including peptide orprotein antigens, live or killed viruses, dendritic cell vaccines,autologous cellular vaccines and polysaccharide conjugates in bothprophylactic and therapeutic vaccines. More importantly it enhancesdendritic cell maturation and differentiation, resulting in enhancedactivation of T_(H1) cells and strong cytotoxic T-lymphocyte (CTL)generation, even in the absence of CD4 T cell help. The T_(H1) biasinduced by TLR9 stimulation is maintained even in the presence ofvaccine adjuvants such as alum or incomplete Freund's adjuvant (IFA)that normally promote a T_(H2) bias. CpG oligonucleotides show evengreater adjuvant activity when formulated or co-administered with otheradjuvants or in formulations such as microparticles, nanoparticles,lipid emulsions or similar formulations, which are especially necessaryfor inducing a strong response when the antigen is relatively weak. Theyalso accelerate the immune response and enable the antigen doses to bereduced by approximately two orders of magnitude, with comparableantibody responses to the full-dose vaccine without CpG in someexperiments (Krieg, 2006). U.S. Pat. No. 6,406,705 B1 describes thecombined use of CpG oligonucleotides, non-nucleic acid adjuvants and anantigen to induce an antigen-specific immune response. A CpG TLR9antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen(Berlin, Germany) which is a preferred component of the pharmaceuticalcomposition of the present invention. Other TLR binding molecules suchas RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used.

Other examples for useful adjuvants include, but are not limited tochemically modified CpGs (e.g. CpR, Idera), dsRNA analogues such asPoly(I:C) and derivates thereof (e.g. AmpliGen®, Hiltonal®, poly-(ICLC),poly(IC-R), poly(I:C12U), non-CpG bacterial DNA or RNA as well asimmunoactive small molecules and antibodies such as cyclophosphamide,sunitinib, Bevacizumab®, celebrex, NCX-4016, sildenafil, tadalafil,vardenafil, sorafenib, temozolomide, temsirolimus, XL-999, CP-547632,pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodiestargeting key structures of the immune system (e.g. anti-CD40,anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which may acttherapeutically and/or as an adjuvant. The amounts and concentrations ofadjuvants and additives useful in the context of the present inventioncan readily be determined by the skilled artisan without undueexperimentation.

Preferred adjuvants are imiquimod, resiquimod, GM-CSF, cyclophosphamide,sunitinib, bevacizumab, interferon-alpha, CpG oligonucleotides andderivates, poly-(I:C) and derivates, RNA, sildenafil, and particulateformulations with PLG or virosomes.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod,resiquimod, and interferon-alpha.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), cyclophosphamide, immiquimodand resiquimod.

In a preferred embodiment of the pharmaceutical composition according tothe invention, the adjuvant is cyclophosphamide, imiquimod orresiquimod.

Even more preferred adjuvants are Montanide IMS 1312, Montanide ISA 206,Montanide ISA 50V, Montanide ISA-51, poly-ICLC (Hiltonal®) and anti-CD40mAB or combinations thereof.

This composition is used for parenteral administration, such assubcutaneous, intradermal, intramuscular or oral administration. Forthis, the peptides and optionally other molecules are dissolved orsuspended in a pharmaceutically acceptable, preferably aqueous carrier.In addition, the composition can contain excipients, such as buffers,binding agents, blasting agents, diluents, flavours, lubricants, etc.The peptides can also be administered together with immune stimulatingsubstances, such as cytokines. An extensive listing of excipients thatcan be used in such a composition, can be, for example, taken from A.Kibbe, Handbook of Pharmaceutical Excipients, 3^(rd) Ed., 2000, AmericanPharmaceutical Association and pharmaceutical press. The composition canbe used for a prevention, prophylaxis and/or therapy of adenomateous orcancerous diseases. Exemplary formulations can be found in, for example,EP2112253.

Nevertheless depending on the number and the physico-chemicalcharacteristics of the peptides of the invention further research isneeded to provide formulations for specific combinations of peptides,especially combinations with more than 20 peptides that are stable formore than 12 to 18 months.

The present invention provides a medicament that useful in treatingcancer, in particular AML, Chronic lymphoid leukemia (CLL) and otherhematological malignancies.

The present invention is further directed at a kit comprising:

(a) a container containing a pharmaceutical composition as describedabove, in solution or in lyophilized form;

(b) optionally a second container containing a diluent or reconstitutingsolution for the lyophilized formulation; and

(c) optionally, instructions for (i) use of the solution or (ii)reconstitution and/or use of the lyophilized formulation.

The kit may further comprise one or more of (iii) a buffer, (iv) adiluent, (v) a filter, (vi) a needle, or (v) a syringe. The container ispreferably a bottle, a vial, a syringe or test tube; and it may be amulti-use container. The pharmaceutical composition is preferablylyophilized.

Kits of the present invention preferably comprise a lyophilizedformulation of the present invention in a suitable container andinstructions for its reconstitution and/or use. Suitable containersinclude, for example, bottles, vials (e.g. dual chamber vials), syringes(such as dual chamber syringes) and test tubes. The container may beformed from a variety of materials such as glass or plastic. Preferablythe kit and/or container contain/s instructions on or associated withthe container that indicates directions for reconstitution and/or use.For example, the label may indicate that the lyophilized formulation isto be reconstituted to peptide concentrations as described above. Thelabel may further indicate that the formulation is useful or intendedfor subcutaneous administration.

The container holding the formulation may be a multi-use vial, whichallows for repeat administrations (e.g., from 2-6 administrations) ofthe reconstituted formulation. The kit may further comprise a secondcontainer comprising a suitable diluent (e.g., sodium bicarbonatesolution).

Upon mixing of the diluent and the lyophilized formulation, the finalpeptide concentration in the reconstituted formulation is preferably atleast 0.15 mg/mL/peptide (=75 μg) and preferably not more than 3mg/mL/peptide (=1500 μg). The kit may further include other materialsdesirable from a commercial and user standpoint, including otherbuffers, diluents, filters, needles, syringes, and package inserts withinstructions for use.

Kits of the present invention may have a single container that containsthe formulation of the pharmaceutical compositions according to thepresent invention with or without other components (e.g., othercompounds or pharmaceutical compositions of these other compounds) ormay have distinct container for each component.

Preferably, kits of the invention include a formulation of the inventionpackaged for use in combination with the co-administration of a secondcompound (such as adjuvants (e.g. GM-CSF), a chemotherapeutic agent, anatural product, a hormone or antagonist, an anti-angiogenesis agent orinhibitor, a apoptosis-inducing agent or a chelator) or a pharmaceuticalcomposition thereof. The components of the kit may be pre-complexed oreach component may be in a separate distinct container prior toadministration to a patient. The components of the kit may be providedin one or more liquid solutions, preferably, an aqueous solution, morepreferably, a sterile aqueous solution. The components of the kit mayalso be provided as solids, which may be converted into liquids byaddition of suitable solvents, which are preferably provided in anotherdistinct container.

The container of a therapeutic kit may be a vial, test tube, flask,bottle, syringe, or any other means of enclosing a solid or liquid.Usually, when there is more than one component, the kit will contain asecond vial or other container, which allows for separate dosing. Thekit may also contain another container for a pharmaceutically acceptableliquid. Preferably, a therapeutic kit will contain an apparatus (e.g.,one or more needles, syringes, eye droppers, pipette, etc.), whichenables administration of the agents of the invention that arecomponents of the present kit.

The present formulation is one that is suitable for administration ofthe peptides by any acceptable route such as oral (enteral), nasal,ophthal, subcutaneous, intradermal, intramuscular, intravenous ortransdermal. Preferably the administration is s.c., and most preferablyi.d. Administration may be by infusion pump.

Since the peptides of the invention were isolated from CLL, themedicament of the invention is preferably used to treat CLL. In apreferred embodiment, since the peptides of the invention derived from aprotein selected from the group consisting of APOBEC3D, CDK14, RASGRF1,CDCA7L, CELSR1, AKAP2, CTDP1, DNMBP, TAGAP, ABCA6, DMXL1, PARP3,TP53I11, B4GALT1, IRF9, KDM2B, TBC1D22A, ZNF296, BACH2, PRR12, ZFAND5,ATP5G1, DMD, ARID5B, ZNF638, DDX46, RRM2B, BLNK, HSH2D, ERP44, METTL7A,ELP3, NLRP2, ZC3H12D, NELFE, ATP6V1C1, HLA-DMA, TUFM, EIF6, CKAP4,COBLL1, TMED4, TNFRSF13C, UBL7, CXorf21, ASUN, SL24D1, and TRAF3IP3 wereisolated from CLL, and thus the medicament of the invention ispreferably used to treat CLL.

The present invention further includes a method for producing apersonalized pharmaceutical for an individual patient comprisingmanufacturing a pharmaceutical composition comprising at least onepeptide selected from a warehouse of pre-screened TUMAPs, wherein the atleast one peptide used in the pharmaceutical composition is selected forsuitability in the individual patient. Preferably, the pharmaceuticalcomposition is a vaccine. The method could also be adapted to produce Tcell clones for down-stream applications such as TCR isolations.

A “personalized pharmaceutical” shall mean specifically tailoredtherapies for one individual patient that will only be used for therapyin such individual patient, including actively personalized cancervaccines and adoptive cellular therapies using autologous patienttissue.

As used herein, the term “warehouse” shall refer to a group of peptidesthat have been pre-screened for immunogenicity and over-presentation ina particular tumour type. The term “warehouse” is not intended to implythat the particular peptides included in the vaccine have beenpre-manufactured and stored in a physical facility, although thatpossibility is contemplated. It is expressly contemplated that thepeptides may be manufactured de novo for each individualized vaccineproduced, or may be pre-manufactured and stored.

The warehouse (e.g. in the form of a database) is composed oftumour-associated peptides which were highly overexpressed in the tumourtissue of several HLA-A, HLA-B and HLA-C positive CLL patients analyzed(see tables above). It contains MHC class I and MHC class II peptides.In addition to the tumor associated peptides collected from several GBMtissues, the warehouse may contain an HLA-A*02 and an HLA-A*24 markerpeptide. These peptides allow comparison of the magnitude of T-cellimmunity induced by TUMAPS in a quantitative manner and hence allowimportant conclusion to be drawn on the capacity of the vaccine toelicit anti-tumor responses. Secondly, it functions as an importantpositive control peptide derived from a “non-self” antigen in the casethat any vaccine-induced T-cell responses to TUMAPs derived from “self”antigens in a patient are not observed. And thirdly, it may allowconclusions to be drawn, regarding the status of immunocompetence of thepatient population.

HLA class I and II TUMAPs for the warehouse are identified by using anintegrated functional genomics approach combining gene expressionanalysis, mass spectrometry, and T-cell immunology. The approach assuresthat only TUMAPs truly present on a high percentage of tumours but notor only minimally expressed on normal tissue, are chosen for furtheranalysis. For peptide selection, CLL samples from patients and bloodfrom healthy donors were analyzed in a stepwise approach:

1. HLA ligands from the malignant material were identified by massspectrometry

2. Genome-wide messenger ribonucleic acid (mRNA) expression analysis bymicroarrays was used to identify genes over-expressed in the malignanttissue (CLL) compared with a range of normal organs and tissues

3. Identified HLA ligands were compared to gene expression data.Peptides encoded by selectively expressed or over-expressed genes asdetected in step 2 were considered suitable TUMAP candidates for amulti-peptide vaccine.

4. Literature research was performed in order to identify additionalevidence supporting the relevance of the identified peptides as TUMAPs

5. The relevance of over-expression at the mRNA level was confirmed byredetection of selected TUMAPs from step 3 on tumor tissue and lack of(or infrequent) detection on healthy tissues

6. To assess whether an induction of in vivo T-cell responses by theselected peptides may be feasible, in vitro immunogenicity assays wereperformed using human T cells from healthy donors as well as from CLLpatients.

In an aspect, the peptides are pre-screened for immunogenicity beforebeing included in the warehouse. By way of example, and not limitation,the immunogenicity of the peptides included in the warehouse isdetermined by a method comprising in vitro T-cell priming throughrepeated stimulations of CD8+ T cells from healthy donors withartificial antigen presenting cells loaded with peptide/MHC complexesand anti-CD28 antibody.

This method is preferred for rare cancers and patients with a rareexpression profile. In contrast to multi-peptide cocktails with a fixedcomposition as currently developed the warehouse allows a significantlyhigher matching of the actual expression of antigens in the tumour withthe vaccine. Selected single or combinations of several “off-the-shelf”peptides will be used for each patient in a multitarget approach. Intheory an approach based on selection of e.g. 5 different antigenicpeptides from a library of 50 would already lead to approximately 17million possible drug product (DP) compositions.

In an aspect, the peptides are selected for inclusion in the vaccinebased on their suitability for the individual patient based on themethod according to the present invention as described herein, and asfollows.

The HLA phenotype, transcriptomic and peptidomic data will be gatheredfrom the patient's tumour material and blood samples to identify themost suitable peptides for each patient containing warehouse andpatient-unique (ie. mutated) TUMAPs. Those peptides will be chosen,which are selectively or over-expressed in the patients tumor and, wherepossible, showed strong in vitro immunogenicity if tested with thepatients individual PBMCs.

Preferably, the peptides included in the vaccine are identified by amethod comprising: (a) identifying tumour-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; (b) comparingthe peptides identified in (a) with a warehouse (database) of peptidesas described above; and (c) selecting at least one peptide from thewarehouse (database) that correlates with a tumour-associated peptideidentified in the patient. For example, the TUMAPs presented by thetumor sample are identified by: (a1) comparing expression data from thetumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and (a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor. Preferably, the sequences of MHCligands are identified by eluting bound peptides from MHC moleculesisolated from the tumor sample, and sequencing the eluted ligands.Preferably, the tumor sample and the normal tissue are obtained from thesame patient.

In addition to, or as an alternative to, selecting peptides using awarehousing (database) model, TUMAPs may be identified in the patient denovo and then included in the vaccine. As one example, candidate TUMAPsmay be identified in the patient by (al) comparing expression data fromthe tumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and (a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor. As another example, proteins may beidentified containing mutations that are unique to the tumor samplerelative to normal corresponding tissue from the individual patient, andTUMAPs can be identified that specifically target the mutation. Forexample, the genome of the tumour and of corresponding normal tissue canbe sequenced by whole genome sequencing: For discovery of non-synonymousmutations in the protein-coding regions of genes, genomic DNA and RNAare extracted from tumour tissues and normal non-mutated genomicgermline DNA is extracted from peripheral blood mononuclear cells(PBMCs). The applied NGS approach is confined to the re-sequencing ofprotein coding regions (exome re-sequencing). For this purpose, exonicDNA from human samples is captured using vendor-supplied targetenrichment kits, followed by sequencing with e.g. a HiSeq2000(Illumina). Additionally, tumour mRNA is sequenced for directquantification of gene expression and validation that mutated genes areexpressed in the patients' tumours. The resultant millions of sequencereads are processed through software algorithms. The output listcontains mutations and gene expression. Tumour-specific somaticmutations are determined by comparison with the PBMC-derived germlinevariations and prioritized. The de novo identified peptides may then betested for immunogenicity as described above for the warehouse, andcandidate TUMAPs possessing suitable immunogenicity are selected forinclusion in the vaccine.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumour-associated peptides (TUMAPs)presented by a tumor sample from the individual patient by the methodsdescribed above; (b) comparing the peptides identified in a) with awarehouse of peptides that have been prescreened for immunogenicity andoverpresentation in tumors as compared to corresponding normal tissue;(c) selecting at least one peptide from the warehouse that correlateswith a tumour-associated peptide identified in the patient; and (d)optionally, selecting at least one peptide identified de novo in (a)confirming its immunogenicity.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumour-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; and (b)selecting at least one peptide identified de novo in (a) and confirmingits immunogenicity.

Once the peptides are selected, the vaccine is manufactured.

The vaccine preferably is a liquid formulation consisting of theindividual peptides dissolved in 33% DMSO.

Each peptide to be included into a product is dissolved in DMSO. Theconcentration of the single peptide solutions has to be chosen dependingon the number of peptides to be included into the product. The singlepeptide-DMSO solutions are mixed in equal parts to achieve a solutioncontaining all peptides to be included in the product with aconcentration of ˜2.5 mg/ml per peptide. The mixed solution is thendiluted 1:3 with water for injection to achieve a concentration of 0.826mg/ml per peptide in 33% DMSO. The diluted solution is filtered througha 0.22 μm sterile filter. The final bulk solution is obtained.

Final bulk solution is filled into vials and stored at −20° C. untiluse. One vial contains 700 μL solution containing 0.578 mg of eachpeptide. Of this, 500 μL (approx. 400 μg per peptide) will be appliedfor intradermal injection.

The present invention will now be described in the following examplesthat describe preferred embodiments thereof, nevertheless, without beinglimited thereto. For the purposes of the present invention, allreferences as cited herein are incorporated by reference in theirentireties.

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1a-1d show the HLA surface expression of primary CLL samples.(FIG. 1a ) HLA class I and (FIG. 1b ) HLA class II expression ofCD5⁺CD19⁺ CLL cells compared to autologous CD5⁻CD19⁺ B cells in 7primary CLL samples. Data are expressed as mean±s.d. of triplicateexperiments. (FIG. 1c ) Mean HLA class I and (FIG. 1d ) HLA class IIexpression CD5⁺CD19⁺ CLL cells compared to autologous CD5⁻CD19⁺ B cells(n=7). *P<0.01 Abbreviations: UPN, uniform patient number

FIGS. 2a-2f show the identification of a novel category oftumor-associated antigens by HLA ligandome profiling. (FIG. 2a ) Overlapof HLA class I ligand source proteins of primary CLL samples (n=30) andHV PBMC (n=30). (FIG. 2b ) Comparative profiling of HLA class I ligandsource proteins based on the frequency of HLA restricted representationin CLL and HV PBMC ligandomes. Frequencies [%] of CLL patients/HVspositive for HLA restricted presentation of the respective sourceprotein (x-axis) are indicated on the y-axis. The box on the left-handside highlights the subset of source proteins showing CLL-exclusiverepresentation in >20% of patients (LiTAAs: ligandome-derivedtumor-associated antigens). (FIG. 2c ) Representation of publishedCLL-associated antigens in HLA class I ligandomes. Bars indicaterelative representation [%] of respective antigens by HLA class Iligands in CLL and HV PBMC. Dashed lines separate the antigens intothree groups according to their degree of CLL-association. (FIG. 2d )Source protein overlaps of CLL samples from different stages of disease(Binet A (n=9), Binet B (n=7), Binet C (n=14)). (FIG. 2e ) Heatmapanalysis of the representation frequencies [%] of LiTAAs acrossdifferent disease stages (Binet A-C, as in (FIG. 2d )) (FIG. 2f )Heatmap analysis of LiTAA representation [%] on primary CLL samples withdel17p (n=5) and without del17p (n=25). Abbreviations: CLL, chroniclymphocytic leukemia; HV, healthy volunteer

FIGS. 3a-3e show that LiTAAs are specifically recognized by CLL patientimmune responses. (FIG. 3a ) HLA class I LiTAAs and corresponding LiTAPs(3 HLA-A*03, 5 HLA-A*02, 5 HLA-B*07) functionally evaluated in IFNγELISPOT assays. Absolute numbers and frequencies of peptide-specificimmune recognition by CLL patient PBMC are summarized in the right handcolumn. (FIG. 3b ) Example of A*03 LiTAPs evaluated in ELISPOT using HVPBMC as a control. An EBV epitope mix containing 4 frequently recognizedpeptides ( . . . ) was used as positive control, HIV GAG₁₈₋₂₆A*03peptide served as negative control. (FIG. 3c ) Example of ELISPOT assaysusing HLA-A*03 LiTAPs (n=3) on PBMC of 3 different CLL patients. Resultsare shown for immunoreactive LiTAPs. EBV epitope mix served as positivecontrol, HIV GAG₁₈₋₂₆ A*03 peptide as negative control. (FIG. 3d )Example of HLA-A*03 benign tissue-derived LiBAPs (n=3) tested on CLLpatient PBMC as internal control for the target selection strategy. EBVepitope mix served as positive control, HIV GAG₁₈₋₂₆ A*03 peptide asnegative control. (FIG. 3e ) Scatterplot of the allele-adjustedfrequencies of LiTAP presentation in CLL ligandomes (as detected by MS)and the corresponding allele-adjusted frequencies of immune recognitionby CLL patient PBMC in IFNγ ELISPOT. Data points are shown for the 14/15LiTAPs showing immune recognition. Abbreviations: LiTAP,ligandome-derived tumor-associated peptide; HV, healthy volunteer; neg.,negative; pos., positive; UPN, uniform patient number; LiBAP,ligandome-derived benign tissue-associated peptide; MS, massspectrometry.

FIGS. 4a-4g show the identification of additional/synergistic HLA classII LiTAAs and LiTAPs. (FIG. 4a ) Overlap of HLA class II ligand sourceproteins of primary CLL samples (n=20) and HV PBMC (n=13). (FIG. 4b )Comparative profiling of HLA class II ligand source proteins based onthe frequency of HLA restricted representation in CLL and HV PBMCligandomes. Frequencies [%] of CLL patients/HVs positive for HLArestricted presentation of the respective source protein (x-axis) areindicated on the y-axis. The box on the left-hand side highlights thesubset of source proteins showing CLL-exclusive representation in >20%of patients (LiTAAs: ligandome-derived tumor-associated antigens). (FIG.4c ) HLA class II LiTAAs and corresponding LiTAPs (n=6) functionallyevaluated in IFNγ ELISPOT assays. Absolute numbers and frequencies ofpeptide-specific immune recognition by CLL patient PBMC are summarizedin the right hand column. (FIG. 4d ) Example of HLA class II LiTAPsevaluated in ELISPOT using HV PBMC as a control. PHA was used aspositive control. FLNA₁₆₆₉₋₁₆₈₃ HLA-DR peptide served as negativecontrol. (FIG. 4e ) Example of ELISPOT assays using HLA class II LiTAPs(n=6) on PBMC of 3 different CLL patients. Results are shown forimmunoreactive LiTAPs. PHA was used as positive control, FLNA₁₆₆₉₋₁₆₈₃HLA-DR peptide served as negative control. (FIG. 4f ) Overlap analysisof CLL-exclusive HLA class I and HLA class II ligand source proteins forshared/synergistic vaccine targets. (FIG. 4g ) Heatmap analysis of the132 shared HLA class I/II LiTAAs (identified in (FIG. 4d )). The twosource proteins showing representation in ≥20% of both, HLA class I andII CLL patient ligandomes are specified.

FIGS. 5a-5c show the longitudinal HLA class I ligandome analysis of CLLpatients undergoing chemo-/immunotherapy. Volcano-Plots of the relativeabundances of ligands in the HLA class I ligandomes of patients aftertreatment compared to their respective abundance prior to therapy (ratiopost therapy/pre therapy). Dashed lines indicate the thresholds forsignificant changes in abundance (>2-fold ratio, p<0.05), withsignificantly up-regulated ligands in the upper-right and significantlydown-regulated ligands in the upper-left. Frequencies of significantlyregulated ligands are specified in the respective quadrants. LiTAPsshowing significant regulation over the course of therapy are marked inred and their sequences are specified. (FIG. 5a ) Analysis of a CLLpatient ligandome prior to therapy and 48h/24h after treatment withrituximab/bendamustin (375 mg/m²/90 mg/m²). 1/28 (3.6%) of detectableLiTAPs showed significant changes in abundance. (FIG. 5b ) Analysis of aCLL patient ligandome prior to therapy and after the first 7 days oftreatment with alemtuzumab (3 doses of alemtuzumab, 10 mg, 20 mg and 30mg on day 1, 3 and 5; ligandome analysis on day 7). 3/24 (12.5%) ofdetectable LiTAPs showed significant changes in abundance. (FIG. 5c )Analysis of a CLL patient ligandome prior to therapy and 24h aftertreatment with 300 mg ofatumumab. 2/10 (20.0%) of detectable LiTAPsshowed significant changes in abundance.

FIGS. 6a and 6b show the retrospective survival analysis of CLL patientswith respect to their immune recognition of LiTAPs. (FIG. 6a ) KaplanMeier plot of the overall survival of 44 CLL patients. (FIG. 6b )Overall survival of subjects evaluated for LiTAP-specific immuneresponses grouped as follows: black, CLL patients showing immuneresponses to >1 LiTAPs (n=10). Red, CLL patients showing immunereactions to 0-1 LiTAPs (n=34).

FIG. 7 shows the saturation analysis of HLA class I ligand sourceprotein identifications in CLL patients. Number of unique HLA ligandsource protein identifications as a function of total HLA ligand sourceprotein identifications in 30 CLL patients. Exponential regressionallowed for the robust calculation (R²=0.9912) of the maximum attainablenumber of different source protein identifications (dashed line). Thedotted line depicts the source proteome coverage achieved in our CLLpatient cohort.

FIGS. 8a-8f show that HLA-A*02 and B*07 LiTAPs are specificallyrecognized by CLL patient immune responses. (FIG. 8a ) Example ofHLA-A*02 (n=3) and (FIG. 8 d) HLA-B*07 (n=3) benign tissue-derivedLiBAPs tested on CLL patient PBMC as internal control for the targetselection strategy. EBV epitope mix served as positive control, HIVXX_(xx-xx) A*02 and HIV XX_(xx-xx) HLA-B*07 peptide served as negativecontrol, respectively. (FIG. 8b ) Example of HLA-A*02 (n=6) and (FIG. 8e) HLA-B*07 (n=5) LiTAPs evaluated in ELISPOT assays using HV PBMC as acontrol. Positive and negative controls as described in (FIG. 8a ).(FIG. 8c ) Example of ELISPOT assays using HLA-A*02 (n=6) and (FIG. 8f )HLA-B*07 (n=5) LiTAPs on PBMC of 3 different HLA-matched CLL patients,each. Results are shown for immunoreactive LiTAPs. Positive and negativecontrols as described in (FIG. 8a ). Abbreviations: LiBAP,ligandome-derived benign tissue-associated peptide; LiTAP,ligandome-derived tumor-associated peptide; HV, healthy volunteer; neg.,negative; pos., positive; UPN, uniform patient number.

FIGS. 9a and 9b show the intracellular cytokine and tetramer staining ofHLA-A*03 LiTAP specific CLL patient T cells. (FIG. 9a ) Intracellularstaining for IFNγ and TNFα of P_(A*03) ³ (DMXL1₁₂₇₁₋₁₂₇₉ SSSGLHPPK (SEQID NO: 77) stimulated CLL patient PBMC. PMA/ionomycin served as positivecontrol, HIV GAG₁₈₋₂₆ A*03 peptide as negative control. (FIG. 9b )Tetramer staining of CLL patient CD8⁺ T cells with P_(A*03) ³(DMXL1₁₂₇₁₋₁₂₇₉ SSSGLHPPK (SEQ ID NO: 77)) tetramers. As control,tetramer staining with the non-recognized P_(A*02) ¹ (ABCA6₁₂₇₀₋₁₂₇₈ILDEKPVII (SEQ ID NO: 63) in the same patient is shown.

FIGS. 10a-10d show the quantification of HLA surface expression onprimary CLL cells from patients undergoing chemo-/immunotherapy. HLAsurface expression on CD5⁺CD19⁺ CLL cells was quantified by flowcytometry, before and after therapy. Data are expressed as mean±s.d. oftriplicate experiments. (FIG. 10a ) HLA class I and (FIG. 10b ) HLAclass II surface expression on primary CLL cells of 4 patients prior totherapy and 24h after treatment with rituximab. (FIG. 10c ) HLA class Iand (FIG. 10d ) HLA class II surface expression on primary CLL cells ofa patient prior to therapy, 72h (10 mg) and 7d (60 mg) after treatmentwith alemtuzumab. *P<0.01 Abbreviations: UPN, uniform patient number; h,hour; d, day.

FIG. 11 shows the over-presentation of peptide ILDEKPVII (SEQ ID NO: 63)in normal tissues as compared to CLL samples. Shown are only samples onwhich the peptide was detected. The test panel included 12 CLL samplesand the following normal samples: 1×adipose tissue, 3×adrenal gland,6×artery, 5×bone marrow, 7×brain, 3×breast, 5×nerve, 13×colon,7×esophagus, 2×gallbladder, 5×heart, 12×kidney, 20×liver, 44×lung,3×lymph node, 4×peripheral blood mononuclear cells, 2×ovary, 6×pancreas,1×peritoneum, 3×pituitary, 2×placenta, 3×pleura, 3×prostate, 6×rectum,7×salivary gland, 4×skeletal muscle, 5×skin, 3×small intestine,4×spleen, 5×stomach, 4×testis, 3×thymus, 3×thyroid gland, 3×trachea,2×ureter, 5×urinary bladder, 2×uterus, 2×vein.

EXAMPLES Example 1

Identification and Quantitation of Tumor Associated Peptides Presentedon the Cell Surface

Tissue Samples

Patients' tumor samples were provided by University of Tübingen,Tübingen, Germany. Written informed consents of all patients had beengiven. For ligandome analysis, PBMC from CLL patients (>80% CLL cellfrequency) as well as PBMC from healthy volunteers (HVs) were isolatedby density gradient centrifugation. Informed consent was obtained inaccordance with the Helsinki protocol. This study was performedaccording to the guidelines of the local ethics committee. HLA typingwas carried out by the Department of Hematology and Oncology, Tübingen.Samples were stored at −80° C. until further use.

Quantification of HLA Surface Expression

For comparison with healthy autologous B lymphocytes, quantification ofHLA surface expression was performed in patient samples containing atleast 0.5% CD5⁻CD19⁺ normal B cells. HLA surface expression was analyzedusing the QIFIKIT® quantitative flow cytometric assay (Dako) accordingto the manufacturer's instructions. In brief, triplicates of each samplewere stained with the pan-HLA class I specific monoclonal antibody (mAb)W6/32, HLA-DR specific mAb L243 (both produced in house) or IgG isotypecontrol (BioLegend), respectively. Surface marker staining was carriedout with directly labeled CD3 (BD), CD5 (BD) and CD19 (BD) antibodies.7-AAD (BioLegend) was added as viability marker immediately prior toflow cytometric analysis on a FACSCanto Analyzer (BD).

Isolation of HLA Peptides from Tissue Samples

HLA class I and II molecules were isolated employing standardimmunoaffinity purification as described previously. In brief,snap-frozen cell pellets were lysed in 10 mM CHAPS/PBS (AppliChem, St.Louis, Mo., USA/Gibco, Carlsbad, Calif., USA) containing 1×proteaseinhibitor (Complete, Roche, Basel, Switzerland). HLA molecules weresingle-step purified using the pan-HLA class I specific mAb W6/32 andthe pan-HLA class II specific mAb Tü39 respectively, covalently linkedto CNBr-activated sepharose (GE Healthcare, Chalfont St Giles, UK).HLA:peptide complexes were eluted by repeated addition of 0.2%trifluoroacetic acid (TFA, Merck, Whitehouse Station, N.J., USA).Elution fractions E1-E8 were pooled and free HLA ligands were isolatedby ultrafiltration using centrifugal filter units (Amicon, Millipore,Billerica, Mass., USA). HLA ligands were extracted and desalted from thefiltrate using ZipTip C18 pipette tips (Millipore). Extracted peptideswere eluted in 35 μl of 80% acetonitrile (ACN, Merck)/0.2% TFA,centrifuged to complete dryness and resuspended in 25 μl of 1% ACN/0.05%TFA. Samples were stored at −20° C. until analysis by LC-MS/MS.

Analysis of HLA Ligands by LC-MS/MS

Peptide samples were separated by reversed-phase liquid chromatography(nanoUHPLC, UltiMate 3000 RSLCnano, ThermoFisher, Waltham, Mass., USA)and subsequently analyzed in an on-line coupled LTQ Orbitrap XL hybridmass spectrometer (ThermoFisher). Samples were analyzed in 5 technicalreplicates. Sample volumes of 5 μl (sample shares of 20%) were injectedonto a 75 μm×2 cm trapping column (Acclaim PepMap RSLC, ThermoFisher) at4 μl/min for 5.75 min. Peptide separation was subsequently performed at50° C. and a flow rate of 175 nl/min on a 50 μm×50 cm separation column(Acclaim PepMap RSLC, ThermoFisher) applying a gradient ranging from2.4-32.0% of ACN over the course of 140 min. Eluting peptides wereionized by nanospray ionization and analyzed in the mass spectrometerimplementing a top 5 CID (collision induced dissociation) methodgenerating fragment spectra for the 5 most abundant precursor ions inthe survey scans. Resolution was set to 60,000. For HLA class I ligands,the mass range was limited to 400-650 m/z with charge states 2 and 3permitted for fragmentation. For HLA class II, a mass range of 300-1,500m/z was analyzed with charge states≥2 allowed for fragmentation.

Database Search and Spectral Annotation

For data processing, the software Proteome Discoverer (v1.3,ThermoFisher) was used to integrate the search results of the Mascotsearch engine (Mascot 2.2.04, Matrix Science) against the human proteomeas comprised in the Swiss-Prot database (release: Sep. 27th 2013; 20,279 reviewed protein sequences contained). The search combined data oftechnical replicates and was not restricted by enzymatic specificity.Precursor mass tolerance was set to 5 ppm, fragment mass tolerance to0.5 Da. Oxidized methionine was allowed as a dynamic modification. Falsediscovery rates (FDR) were determined by the Percolator algorithm basedon processing against a decoy database consisting of the shuffled targetdatabase. FDR was set at a target value of q≤0.05 (5% FDR).Peptide-spectrum matches (PSMs) with q≤0.05 were filtered according toadditional, orthogonal parameters, to ensure spectral quality andvalidity. Mascot scores were filtered to ≥20. For HLA class I, peptidelengths were limited to 8-12 amino acids (aa) of length. For HLA classII, peptides were limited to 12-25 aa length. Protein grouping wasdisabled, allowing for multiple annotations of peptides (e.g. conservedsequences mapping into multiple proteins). For quality control, yieldthresholds of ≥300 unique HLA class I ligands and ≥00 unique HLA classII ligands per sample were applied. HLA annotation was performed usingSYFPEITHI or an extended in-house database.

Longitudinal Analysis of CLL Patient Ligandomes Over the Course ofTherapy

For label-free quantification (LFQ) of the relative HLA ligandabundances over the course of therapy, the injected peptide amounts ofpaired samples were normalized and LC-MS/MS analysis was performed in 5technical replicates for each sample.

In brief, relative amounts of substance of paired samples werecalculated from average precursor ion intensities determined indose-finding mass spectrometry runs and adjusted accordingly bydilution. Relative quantification of HLA ligands was performed bycalculating the area under the curve of the corresponding precursorextracted ion chromatograms (XIC) using Proteome Discoverer 1.3. Theratios of the mean areas of the individual peptides in the 5 LFQ-MS runsof each sample were calculated and two-tailed t-tests were performedusing an in-house Matlab script (v8.2, Mathworks).

Peptide Synthesis

The automated peptide synthesizer EPS221 (Abimed) was used to synthesizepeptides using the 9-fluorenylmethyl-oxycarbonyl/tert-butyl (Fmoc/tBu)strategy as described. Synthetic peptides were used for validation ofLC-MS/MS identifications as well as for functional experiments.

Amplification of Peptide-Specific T Cells

PBMC from CLL patients and healthy volunteers were cultured in RPMI1640medium (Gibco) supplemented with 10% pooled human serum (PHS, producedin-house), 100 mM β-mercaptoethanol (Roth, Karlsruhe, Germany) and 1%penicillin/streptomycin (GE). For CD8⁺ T cell stimulation, PBMC werethawed and pulsed with 1 μg/ml per peptide. Peptide-pulsed PBMC (5-6×10⁶cells/ml) were cultured at 37° C. and 5% CO₂ for 12 days. On day 0 andday 1.5 ng/ml IL-4 (R&D Systems, Minneapolis, Minn., USA) and 5 ng/mlIL-7 (Promokine, Heidelberg, Germany) were added to the culture medium.On days 3, 5, 7 and 9, 2 ng/ml IL-2 (R&D Systems) were added to theculture medium. Peptide-stimulated PBMC were functionally characterizedby ELISPOT assays on day 12 and by intracellular cytokine staining onday 13 respectively. For CD4⁺ T-cell stimulation, culture was performedas described for CD8⁺ T cells with 2 modifications: pulsing was carriedout with 10 μg/ml of HLA class II peptide and no IL-4 and IL-7 wasadded.

IFN-γ ELISPOT Assay

IFN-γ ELISPOT assays were carried out as described previously (33). Inbrief, 96-well nitrocellulose plates (Millipore) were coated with 1mg/ml IFN-γ mAb (Mabtech, Cincinnati, Ohio, USA) and incubated overnight at 4° C. Plates were blocked with 10% PHS for 2 h at 37° C. 5×10⁵cells/well of pre-stimulated PBMC were pulsed with 1 μg/ml (HLA class I)or 2.5 μg/ml (HLA class II) peptide and incubated for 24-26 h. Readoutwas performed according to manufacturer's instructions. Spots werecounted using an ImmunoSpot S5 analyzer (CTL, Shaker Heights, Ohio,USA). T cell responses were considered to be positive when >15spots/well were counted and the mean spot count per well was at least3-fold higher than the mean number of spots in the negative controlwells (according to the cancer immunoguiding program (CIP) guidelines).

Intracellular IFN-γ and TNF-α Staining

The frequency and functionality of peptide-specific CD8⁺ T cells wasanalyzed by intracellular IFN-γ and TNF-α staining. PBMC were pulsedwith 1 μg/ml of individual peptide and incubated in the presence of 10μg/ml Brefeldin A (Sigma, St. Louis, Mo., USA) and 10 μg/ml GolgiStop(BD) for 6-8 h. Cells were labeled using Cytofix/Cytoperm (BD),CD8-PECy7 (Beckman Coulter, Fullerton, Calif., USA), CD4-APC (BDBioscience), TNF-α-PE (Beckman Coulter) and IFN-γ-FITC (BD). Sampleswere analyzed on a FACS Canto II.

The frequency of peptide-specific CD8⁺ T cells was determined bystaining with anti-CD8 and HLA:peptide-tetramer-PE

Results

Primary CLL Cells Display No Loss or Down-Regulation of HLA ExpressionCompared to Autologous Normal B Cells

HLA loss or down-regulation in malignancies may pose a major limitationfor T cell based immunotherapy. Therefore, as a first step, theinventors determined the HLA expression levels on CD19⁺CD5⁺ CLL cellscompared to autologous CD19⁺CD5⁻ B lymphocytes. HLA surface levels werequantified by flow cytometry in a panel of 7 CLL patients. HLA surfaceexpression levels revealed patient-individual heterogeneity with totalHLA class I molecule counts ranging from ˜42,500-288,500 molecules/cellon CLL cells and ˜32,000-256,500 molecules/cell on normal B cells.Patient individual analysis of HLA surface expression in triplicatesrevealed small, albeit significant differences in expression levels(P<0.01) for 4/7 patients (FIG. 1a ). HLA-DR expression ranged from˜29,000-100,500 on CLL cells and ˜19,500-79,500 on B cells. Minordifferences in HLA-DR levels (P<0.01) were detected for 5/7 patients.Statistical analysis of mean HLA surface expression on CLL cellscompared to normal B cells showed no significant differences in HLAclass I and II expression (FIGS. 1c, 1d ). Taken together, these datademonstrate high levels of HLA class I and II expression on CLL cellswithout evidence of HLA loss or down-regulation compared to normal Bcells.

LC-MS/MS Identifies a Vast Array of Naturally Presented HLA Class I & IILigands

Mapping the HLA class I ligandomes of 30 CLL patients, the inventorswere able to identify a total of 18,844 different peptides representing7,377 source proteins, attaining >95% of maximum attainable coverage(FIG. 7). The numbers of different peptides identified per patientranged from 345-2,497 (mean 1,131). Overall, peptides restricted by morethan 30 different HLA-A and -B alleles (covering >99% of the Caucasianpopulation_ENREF_27) were identified in this study. In the HV cohort of30 PBMC donors, a total of 17,322 unique peptides representing 7,180different source proteins were identified (>90% coverage). The HLAallele distribution in the HV cohort covered 100% of HLA-A and >80% ofHLA-B alleles in the CLL patient cohort.

Analysis of the HLA class II ligandomes was performed for 20 CLLpatients. A total of 5,059 unique peptides representing 1,486 sourceproteins was identified. The HLA class II HV cohort of 13 PBMC donorsyielded 2,046 different peptides representing 756 source proteins.

Comparative Profiling of HLA Class I Ligandomes Reveals a Multitude ofCLL-Associated Antigens

In order to identify novel CLL-associated antigens, the inventorscompared the HLA ligand source proteomes of the CLL and HV cohorts.Overlap analysis of HLA source proteins revealed 2,148 proteins (29.1%of the mapped CLL source proteome) to be exclusively represented in theHLA ligandome of CLL (FIG. 2a ). With the aim of designing a broadlyapplicable off-the-shelf peptide vaccine, the inventors subsequentlyprioritized the selection of potential targets according to thefollowing criteria:

CLL-exclusivity was defined as paramount criterion, followed by rankingof antigens according to frequency of representation in CLL ligandomes(FIG. 2b ). Our platform highlighted 49 source proteins (0.7% of the CLLsource proteome) represented by 225 different HLA ligands showingCLL-exclusive representation in ≥20% of CLL patients. Applying the sameantigen ranking strategy to HV PBMC exclusive antigens, a set of 71ligandome-derived benign tissue-associated antigens (LiBAAs) and the 298corresponding ligands (LiBAPs) were identified for use as internalcontrol in immunological assays.

Apart from broadly represented CLL-LiTAAs suited for the design ofoff-the-shelf vaccines, a second panel of 2,099 CLL-exclusive antigenswith representation frequencies <20% was identified by our platform.These targets lend themselves as repositories for more individualizedtherapeutic approaches.

Detection of Naturally Presented HLA Class I Ligands Derived fromEstablished CLL-Associated Antigens by LC-MS/MS

Alongside the identification of novel CLL-associated antigens, asecondary approach focused on the ranking of the few establishedCLL-antigens within the present dataset of naturally presented HLAligands. The inventors were able to identify 28 different HLA ligandsrepresenting 8 described CLL-associated antigens. Of note, onlyFibromodulin (FMOD₃₂₄₋₃₃₃, RINEFSISSF, HLA-A*23 (SEQ ID NO: 526) showedCLL-exclusive representation, ranking at #437 of CLL-antigens in thepresent dataset, due to low frequency of representation in the CLLpatient cohort. The remaining seven antigens showed representation, bothon CLL and HV PBMC, thus failing to fulfill the paramount criterion ofCLL-exclusivity. However, for CD19, CD20, RHAMM and PRAME,CLL-associated overrepresentation of varying degrees was detected (FIG.2c ).

Comparative Ligandome Profiling Identifies LiTAAs Shared Among DifferentDisease Stages and Risk Strata

In order to assess the applicability of the novel targets acrossdifferent stages of disease, the inventors performed subset-specificligandome profiling comparing patients in disease stages Binet A (n=9),B (n=7) and C (n=14). Overlap analysis of the 2,148 CLL-exclusive sourceproteins found 550 (25.6%) of them shared among at least two stages,with a core group of 137 proteins (6.1%) represented in patients of allthree stages of disease (FIG. 2d ). Of note, 45/49 (91.8%) of LiTAAsbelong to the core group of shared source proteins represented in allthree subsets. Heatmap analysis of the representation frequencies of all49 LiTAAs across Binet stages A, B and C is shown in FIG. 2 e.

Another focus was placed on determining the representation of LiTAAs inthe subsets of high-risk patients carrying the 17p13 deletion (del17p,n=5) as compared to patients without this genetic aberration (no del17p,n=25). The inventors found 77.7% of the identified LiTAAs to berepresented in both subsets (FIG. 2f ). Together, these data support thedevised strategy of cohort-comprising analysis of HLA ligandomes forselection of broadly applicable targets.

Functional Characterization of HLA Class I LiTAPs Reveals CLL-AssociatedImmunoreactivity

In order to evaluate the immunogenicity and specificity of our HLA classI LiTAPs, the inventors next performed 12-day recall IFNγ ELISPOTassays. A panel of 15 LiTAPs (6 A*02, 4 A*03 and 5 B*07 LiTAPs) wasimplemented for stimulation of HLA-matched PBMC obtained from CLLpatients and healthy volunteers (FIG. 3a ). The inventors observed IFNγsecretion for 14/15 (93.3%) of tested LiTAPs in CLL patients (3/4 A*03(FIG. 3c ), 6/6 A*02 and 5/5 B*07 LiTAPs (FIGS. 8c, 8f )), but not inhealthy controls (0/10, FIG. 3b , FIGS. 8b, 8e ). These findings wereconfirmed exemplarily for P_(A*03) ³ (DMXL1₁₂₇₁₋₁₂₇₉ SSSGLHPPK (SEQ IDNO:77)) by tetramer staining of CD8⁺ T cells and intracellular cytokinestaining for IFNγ and TNFα (FIGS. 9a, 9b ). ELISPOT assays usingHLA-matched benign tissue-derived LiBAPs were performed to control forthe CLL-specificity of the observed LiTAP-directed immune recognition inCLL patients. The inventors tested a panel of 9 LiBAPs (3 A*02, 3 A*03,3*B*07) and observed no significant IFNγ secretion in any of the testedCLL patients (0/7 A*03 (FIG. 3d ), 0/10 A*02+ and 0/5 B*07 (FIGS. 8a, 8d)).

For the 14/15 LiTAPs showing immune recognition in 1 or more patients,the inventors calculated the allele-adjusted frequencies of HLArestricted presentation (as detected by LC-MS/MS) and the frequencies ofimmunoreactivity (as detected by ELISPOT) in CLL patients. Strikingly, alinear correlation of these two parameters was observed (Pearson'sr=0.77, R²=0.59, FIG. 3e ). These findings suggest two main points:First, tumor-exclusive representation is prerequisite for immunerecognition. Secondly, frequency of immune recognition can be directlydeduced from the frequency of HLA restricted presentation forimmunoreactive LiTAPs. Together, these data demonstrate the efficacy ofour approach identifying immunologically relevant targets forCLL-specific peptide vaccines.

HLA Class II Ligandome Analysis Identifies Additional CD4⁺ T CellEpitopes for Synergistic Vaccine Design

Because of the important indirect and direct roles CD4⁺ T cells play inanti-cancer immune responses, optimal vaccine design calls for theinclusion of additional HLA class II epitopes. The inventors performedoverlap analysis of CLL and HV PBMC ligandomes and identified 937proteins (63.0% of the identified CLL source proteins) to be exclusivelyrepresented in the ligandomes of CLL patients (FIG. 4a ). Applying thesame antigen-ranking strategy as described for HLA class I, theinventors identified 73 HLA class II LiTAAs represented by 460corresponding LiTAPs (FIG. 4b ). Functional characterization of a panelof 7 HLA class II LiTAPs (FIG. 4c ) in IFNγ ELISPOT assays revealedsignificant IFNγ secretion for 6/7 (85.7%) LiTAPs in CLL patients (FIG.4e ), but not in healthy controls (0/10, FIG. 4d ). Next, the inventorsperformed combined analysis of HLA class I and II ligandomes in order toidentify shared, synergistic targets. Overlap analysis of CLL-exclusivesource proteins revealed 132 proteins to be represented both in HLAclass I and II ligandomes (FIG. 4f ). Heatmap analysis identified 2proteins displaying representation frequencies≥20% in both ligandomes(B4GALT1 (26.7% class I/30.0% class II), HLA-DMA (20.0% class I/20%class II), FIG. 4g ). Strikingly, one of the class I LiTAPs(HLA-DMA₂₀₆₋₂₁₄, HEIDRYTAI, B*18 (SEQ ID NO: 178)) was revealed to becompletely embedded in the corresponding HLA class II LiTAP(VTHEIDRYTAIAY (SEQ ID No. 924)). Together, the inventors identified apanel of class II LiTAPs, which could be verified as T cell epitopes, aswell as an array of potentially synergistic HLA class II ligandscovering class I LiTAAs.

Longitudinal Analysis of CLL Patient Ligandomes Under DifferentTherapeutic Regimens

The scope of peptide based immunotherapy is maintenance therapy anderadication of MRD. As a consequence, peptide vaccination in CLL wouldtake place after standard chemo-/immunotherapy. Therefore, the inventorsanalyzed HLA expression and performed ligandome profiling acrossdifferent time points of CLL patients undergoing different therapeuticregimens.

The inventors quantified HLA class I and II surface expression in 4patients undergoing rituximab treatment (Rt_(0h), Rt_(24h)) and 1patient receiving alemtuzumab (At_(0h), At_(72h), At_(7d), FIGS. 10a-10d). HLA surface expression showed patient-individual heterogeneity withno significant changes in mean HLA class I (Rt_(0h)=50,500,Rt_(24h)=48,000; At_(0h)=42,500, At_(7d)=61,500) and HLA class II(Rt_(0h)=36,500, Rt_(24h)=27,500; At_(0h)=47,000, At_(7d)=55,500)expression over the course of either therapeutic regimen.

Longitudinal HLA class I ligandome profiling was performed in singlepatients undergoing rituximab-bendamustin, alemtuzumab or ofatumumabtreatment, respectively (FIGS. 5a-5c ). Differential presentation(2-fold change, p≤0.05) was observed for 11.1% of HLA class I ligandsunder rituximab-bendamustin treatment, for 21.6% of ligands underofatumumab treatment and for 33.6% of ligands under alemtuzumabtreatment. Overall, LiTAPs representing 8/49 (16.3%) LiTAAs wererevealed to be differentially presented over the course of therapy.Taken together, these data demonstrate stable expression of surface HLAand robust presentation of LiTAPs over the course of differenttherapies.

Immune Responses Against LiTAPs Might be Associated with ImprovedOverall Survival of CLL Patients

As a last step, the inventors performed retrospective survival analysisof 33 CLL patients (FIG. 6a ) analyzed by ELISPOT assays comparing caseswith 0-1 LiTAP-specific (n=23) versus >1 LiTAP-specific (n=10) T cellresponses (FIG. 6b ). In the low-responding cohort 6/23 (26.1%) ofpatients, in the high-responding cohort 0/11 of patients died. Overallsurvival seems to be prolonged in the cohort showing >1 immunereactions.

Example 2

Synthesis of Peptides

All peptides were synthesized using standard and well-established solidphase peptide synthesis using the Fmoc-strategy. After purification bypreparative RP-HPLC, ion-exchange procedure was performed to incorporatephysiological compatible counter ions (for example trifluoro-acetate,acetate, ammonium or chloride).

Identity and purity of each individual peptide have been determined bymass spectrometry and analytical RP-HPLC. After ion-exchange procedurethe peptides were obtained as white to off-white lyophilizates inpurities of 90% to 99.7%.

All TUMAPs are preferably administered as trifluoro-acetate salts oracetate salts, other salt-forms are also possible. For the measurementsof example 4, trifluoro-acetate salts of the peptides were used.

Example 3

MHC Binding Assays

Candidate peptides for T cell based therapies according to the presentinvention were further tested for their MHC binding capacity (affinity).The individual peptide-MHC complexes were produced by peptide-ligandexchange, where a cleavage-sensitive peptide is cleaved, and exchangedwith the peptide of interest as analyzed. Only peptide candidates thatcan effectively bind and stabilize the peptide-receptive MHC moleculesprevent dissociation of the MHC complexes. To determine the yield of theexchange reaction, an ELISA was performed based on the detection of thelight chain (β2m) of stabilized MHC complexes. The assay was performedas generally described in Rodenko et al. (Rodenko et al., Nat Protoc. 1(2006): 1120-1132).

96 well MAXISorp plates (NUNC) were coated over night with 2 ug/mlstreptavidin in PBS at room temperature, washed 4× and blocked for 1 hat 37° C. in 2% BSA containing blocking buffer. RefoldedHLA-A*0201/MLA-001 monomers served as standards, covering the range of15-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction werediluted 100 fold in blocking buffer. Samples were incubated for 1h at37° C., washed four times, incubated with 2 ug/ml HRP conjugatedanti-β2m for 1h at 37° C., washed again and detected with TMB solutionthat is stopped with NH₂SO₄. Absorption was measured at 450 nm.Candidate peptides that show a high exchange yield (preferably higherthan 50%, most preferred higher than 75%) are generally preferred for ageneration and production of antibodies or fragments thereof, and/or Tcell receptors or fragments thereof, as they show sufficient avidity tothe MHC molecules and prevent dissociation of the MHC complexes.

MHC class I binding scores for the peptides as tested were; <20%=+;20%-49%=++; 50%-75%=+++; >=75%=++++

Seq ID Peptide NO. sequence exchange 229 FRVGNVQEL ++++ 239 SENAFYLSP++++

Example 4

In Vitro Immunogenicity for MHC Class I Presented Peptides

In order to obtain information regarding the immunogenicity of theTUMAPs of the present invention, the inventors performed investigationsusing an in vitro T-cell priming assay based on repeated stimulations ofCD8+ T cells with artificial antigen presenting cells (aAPCs) loadedwith peptide/MHC complexes and anti-CD28 antibody. This way theinventors could show immunogenicity for HLA-A*0201 restricted TUMAPs ofthe invention, demonstrating that these peptides are T-cell epitopesagainst which CD8+ precursor T cells exist in humans.

In Vitro Priming of CD8+ T Cells

In order to perform in vitro stimulations by artificial antigenpresenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02leukapheresis products via positive selection using CD8 microbeads(Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtainedfrom the University clinics Mannheim, Germany, after informed consent.

PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium(TCM) until use consisting of RPMI-Glutamax (Invitrogen, Karlsruhe,Germany) supplemented with 10% heat inactivated human AB serum(PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/mlStreptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro,Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7(PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma,Nürnberg, Germany) were also added to the TCM at this step.

Generation of pMHC/anti-CD28 coated beads, T-cell stimulations andreadout was performed in a highly defined in vitro system using fourdifferent pMHC molecules per stimulation condition and 8 different pMHCmolecules per readout condition.

The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung etal., Proc Natl Acad Sci USA 84 (1987): 4611-4615) was chemicallybiotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended bythe manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 μmdiameter streptavidin coated polystyrene particles (Bangs Laboratories,Illinois, USA).

pMHC used for positive and negative control stimulations wereA*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 1017) from modifiedMelan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO.1018), respectively.

800.000 beads/200 μl were coated in 96-well plates in the presence of4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 wereadded subsequently in a volume of 200 μl. Stimulations were initiated in96-well plates by co-incubating 1×10⁶ CD8+ T cells with 2×10⁵ washedcoated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell)for 3 days at 37° C. Half of the medium was then exchanged by fresh TCMsupplemented with 80 U/ml IL-2 and incubating was continued for 4 daysat 37° C. This stimulation cycle was performed for a total of threetimes. For the pMHC multimer readout using 8 different pMHC moleculesper condition, a two-dimensional combinatorial coding approach was usedas previously described (Andersen et al., Nat. Protoc. 7 (2012):891-902) with minor modifications encompassing coupling to 5 differentfluorochromes. Finally, multimeric analyses were performed by stainingthe cells with Live/dead near IR dye (Invitrogen, Karlsruhe, Germany),CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescentpMHC multimers. For analysis, a BD LSRII SORP cytometer equipped withappropriate lasers and filters was used. Peptide specific cells werecalculated as percentage of total CD8+ cells. Evaluation of multimericanalysis was done using the FlowJo software (Tree Star, Oregon, USA). Invitro priming of specific multimer+CD8+ lymphocytes was detected bycomparing to negative control stimulations. Immunogenicity for a givenantigen was detected if at least one evaluable in vitro stimulated wellof one healthy donor was found to contain a specific CD8+ T-cell lineafter in vitro stimulation (i.e. this well contained at least 1% ofspecific multimer+among CD8+ T-cells and the percentage of specificmultimer+ cells was at least 10× the median of the negative controlstimulations).

In Vitro Immunogenicity for CLL Peptides

For tested HLA class I peptides, in vitro immunogenicity could bedemonstrated by generation of peptide specific T-cell lines. As anexemplary result, peptide KFAEEFYSF (SEQ ID NO. 20) led to in vitroT-cell responses in 2 of 5 tested donors.

Example 5

Identification and Quantitation of Tumor Associated Peptides Presentedon the Cell Surface

Tissue Samples:

In addition to the samples used for identification of peptides, anindependent sample set comprising both normal and tumor (CLL) tissueswas used for analysis/confirmation of HLA-A*02-associated peptides ofthe invention. Written informed consents of all patients had been givenbefore surgery or autopsy. Tissues were shock-frozen immediately afterexcision and stored until isolation of TUMAPs at −70° C. or below.

Isolation of HLA Peptides from Tissue Samples

HLA peptide pools from shock-frozen tissue samples were obtained byimmune precipitation from solid tissues according to a slightly modifiedprotocol (Falk et al., Nature 351 (1991): 290-296; Seeger et al.,Immunogenetics 49 (1999): 571-576) using the HLA-A*02-specific antibodyBB7.2, the HLA-A, —B, C-specific antibody W6/32, CNBr-activatedsepharose, acid treatment, and ultrafiltration.

Mass Spectrometry Analyses

The HLA peptide pools as obtained were separated according to theirhydrophobicity by reversed-phase chromatography (nanoAcquity UPLCsystem, Waters) and the eluting peptides were analyzed in LTQ-velos andfusion hybrid mass spectrometers (ThermoElectron) equipped with an ESIsource. Peptide pools were loaded directly onto the analyticalfused-silica micro-capillary column (75 μm i.d.×250 mm) packed with 1.7μm C18 reversed-phase material (Waters) applying a flow rate of 400 nLper minute. Subsequently, the peptides were separated using a two-step180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nLper minute. The gradient was composed of Solvent A (0.1% formic acid inwater) and solvent B (0.1% formic acid in acetonitrile). A gold coatedglass capillary (PicoTip, New Objective) was used for introduction intothe nanoESI source. The LTQ-Orbitrap mass spectrometers were operated inthe data-dependent mode using a TOP5 strategy. In brief, a scan cyclewas initiated with a full scan of high mass accuracy in the orbitrap(R=30 000), which was followed by MS/MS scans also in the orbitrap(R=7500) on the 5 most abundant precursor ions with dynamic exclusion ofpreviously selected ions. Tandem mass spectra were interpreted bySEQUEST and additional manual control. The identified peptide sequencewas assured by comparison of the generated natural peptide fragmentationpattern with the fragmentation pattern of a synthetic sequence-identicalreference peptide.

Label-free relative LC-MS quantitation was performed by ion countingi.e. by extraction and analysis of LC-MS features (Mueller et al.,Proteomics. 7 (2007): 3470-3480). The method assumes that the peptide'sLC-MS signal area correlates with its abundance in the sample. Extractedfeatures were further processed by charge state deconvolution andretention time alignment (Mueller et al., J Proteome. Res 7 (2008):51-61; Sturm et al., BMC. Bioinformatics. 9 (2008): 163). Finally, allLC-MS features were cross-referenced with the sequence identificationresults to combine quantitative data of different samples and tissues topeptide presentation profiles. The quantitative data were normalized ina two-tier fashion according to central tendency to account forvariation within technical and biological replicates. Thus eachidentified peptide can be associated with quantitative data allowingrelative quantification between samples and tissues. In addition, allquantitative data acquired for peptide candidates was inspected manuallyto assure data consistency and to verify the accuracy of the automatedanalysis. For each peptide a presentation profile was calculated showingthe mean sample presentation as well as replicate variations. Theprofiles juxtapose CLL samples to a baseline of normal tissue samples.The presentation profile of an exemplary over-presented peptide is shownin FIG. 11.

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The invention claimed is:
 1. A method of eliciting an immune response ina patient who has cancer, comprising administering to said patient apopulation of activated T cells that selectively recognize cells, whichpresent a peptide consisting of the amino acid sequence of SEQ ID NO:167, wherein said cancer is selected from the group consisting ofchronic lymphoid leukemia (CLL), acute myelogenous leukemia (AML),adrenal gland adrenal cortical adenoma, bone giant cell tumor of bone,bone non-ossifying fibroma, breast carcinoma, colon adenocarcinoma,non-Hodgkin's lymphoma, endometrium adenocarcinoma endometrioid, kidneyangiomyolipoma, kidney carcinoma, kidney oncocytoma, liver focal nodularhyperplasia, liver hepatocellular carcinoma, lymph node Hodgkin'sdisease, lymph node papillary carcinoma of thyroid, medullary carcinomaof thyroid origin, metastatic adenocarcinoma of stomach, neurofibroma,ovary thecoma fibroma, pancreas adenocarcinoma, pancreas microcysticadenoma, parathyroid gland adenoma, rectum adenocarcinoma, skin squamouscell carcinoma, spleen chronic myeloid leukemia, stomachgastrointestinal stromal tumor (GIST), thyroid gland nodularhyperplasia, thyroid gland papillary carcinoma, and uterine cervixsquamous cell carcinoma.
 2. The method of claim 1, wherein the T cellsare autologous to the patient.
 3. The method of claim 1, wherein the Tcells are obtained from a healthy donor.
 4. The method of claim 1,wherein the T cells are obtained from tumor infiltrating lymphocytes orperipheral blood mononuclear cells.
 5. The method of claim 1, whereinthe activated T cells are expanded in vitro.
 6. The method of claim 1,wherein the peptide is in a complex with an MHC molecule.
 7. The methodof claim 6, wherein the MHC molecule is a class I MHC molecule.
 8. Themethod of claim 1, wherein the activated T cells are cytotoxic T cellsproduced by contacting T cells with an antigen presenting cell thatexpresses the peptide in a complex with an MHC class I molecule on thesurface of the antigen presenting cell, for a period of time sufficientto activate said T cell.
 9. The method of claim 8, wherein the antigenpresenting cell is infected with recombinant virus expressing thepeptide.
 10. The method of claim 9, wherein the antigen presenting cellis a dendritic cell or a macrophage.
 11. The method of claim 8, whereinthe contacting is in vitro.
 12. The method of claim 1, wherein thepopulation of activated T cells are administered in the form of acomposition.
 13. The method of claim 12, wherein the composition furthercomprises an adjuvant.
 14. The method of claim 13, wherein the adjuvantis selected from the group consisting of anti-CD40 antibody, imiquimod,resiguimod, GM-CSF, cyclophosphamide, Sunitinib, bevacizumab,interferon-alpha, interferon-beta, CpG oligonucleotides and derivatives,poly-(I:C) and derivatives, RNA, sildenafil, and particulate formationswith poly(lactid co-glycolid) (PLG), virosomes, interleukin (IL)-1,IL-2, IL-4, IL-7, IL-12, IL-13, IL-15, IL-21, and IL-23.
 15. The methodof claim 1, wherein the immune response is capable of killing cancercells that present a peptide consisting of the amino acid sequence ofSEQ ID NO:
 167. 16. The method of claim 15, wherein the immune responsecomprises a cytotoxic T cell response.
 17. The method of claim 1,wherein the cancer is chronic lymphoid leukemia (CLL).
 18. The method ofclaim 1, wherein the cancer is acute myelogenous leukemia (AML).